Peptides 103 (2018) 48–59

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Peptides
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Review

Actinobacteria–Derived peptide antibiotics since 2000 T

a a,⁎ a a a a
Pengchao Zhao , Yun Xue , Weina Gao , Jinghua Li , Xiangyang Zu , Dongliao Fu ,
Shuxiao Fengb, Xuefei Baia, Yanjun Zuoa, Ping Lia
a
College of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, 471023, China
b
College of Chemical Engineering and Pharmacy, Henan University of Science and Technology, Luoyang, 471023, China

A R T I C LE I N FO A B S T R A C T

Keywords: Members of the Actinobacteria, including Streptomyces spp., Kutzneria sp. Actinoplanes spp., Actinomycete sp.,
Actinobacteria Nocardia sp., Brevibacteriumsp.,Actinomadura spp., Micromonospora sp., Amycolatopsis spp., Nonomuraea spp.,
Lipopeptide Nocardiopsis spp., Marinactinospora sp., Rhodococcus sp., Lentzea sp., Actinokineospora sp., Planomonospora sp.,
Thiopeptide Streptomonospora sp., and Microbacterium sp., are an important source of structurally diverse classes of short
Lasso peptide
peptides of ∼30 residues or fewer that will likely play an important role in new antibiotic development and
Antibiotic activity
Structural sequence
discovery. Additionally, many have unique structures that make them recalcitrant to traditional modes of drug
resistance via novel mechanisms, and these are ideal therapeutic tools and potential alternatives to current
antibiotics. The need for novel antibiotic is urgent, and this review summarizes 199 Actinobacteria compounds
published since 2000, including 35 cyclic lipopeptides containing piperazic or pipecolic acids, eight aromatic
peptides, five glycopeptides, 21 bicyclic peptides, 44 other cyclic lipopeptides, five linear lipopeptides, six 2,5-
diketopiperazines, one dimeric peptide, four nucleosidyl peptides, two thioamide-containing peptides, 25
thiopeptides, nine lasso peptides, and 34 typical cyclic peptides. The current and potential therapeutic appli-
cations of these peptides, including their structure, antituberculotic, antibacterial, antifungal, antiviral, anti-
brugia, anti-plasmodial, and anti-trypanosomal activities, are discussed.

1. Introduction
Natural microbial products are an important source of both existing
and new antibiotics [1]. Actinobacteria is one of the dominant bacterial
phyla, and most of its species are free-living micro-organisms that are
ubiquitously found in both aquatic and terrestrial ecosystems. Their
diversity ensures one of the main features of this group: versatility in
the production of biologically active compounds, including new anti-
biotic substances [2]. Representative genera of Actinobacteria include
Streptomyces spp. (S .lydicus, S. drozdowiczii, S. viridochromogenes, S.
hygroscopicus, S. iakyrus, S. spectabilis, S. parvus, S. coelicolor, S. roseos-
porus, S. fradiae, S. albulus, S. malaysiense, S. achromogenes, S. leeu-
wenhoekii, S. sviceus, S. lavendulae, S. alboflavus, S. scopuliridus, S. cur-
acoi, S. ambofaciens, S. canus, and S. globisporus) [3–26], Kutzneria sp.
[27], Actinoplanes spp. (A. friuliensis and A. philippinensis) [28,29], Ac-
tinomycetesp. [30], Nocardia sp. [31], Brevibacterium sp. (B. aureum)
[32], Actinomadura spp. (A. madurae) [33,34], Micromonospora sp. [35],
Amycolatopsis spp. (A. fastidiosa) [36–38], Nonomuraea spp. [39,40],
Nocardiopsis spp. [41,42], Marinactinospora sp. (M. thermotolerans) [43],
Rhodococcus sp. [44,45], Lentzea sp. (L. kentuckyensis) [46], Actinoki-
neospora sp. (A. spheciospongiae) [47], Planomonospora sp. (P. sphaerica)
[48], Streptomonospora sp. (S. alba) [49], Microbacterium sp. [50], and
Thermoactinomyces sp. (T. vulgaris) [51]. Short peptides comprising
∼30 residues or fewer have received much attention because of acting
on novel mechanisms, and they are recalcitrant to traditional modes of
drug resistance [52]. Until now, some of these molecules have been
approved to treat infections caused by Gram-positive pathogens and
Mycobacteria (Table 1) [53–63]. As a result, it is widely believed that
more Actinobacteria-derived peptide antibiotics will be implemented in
the clinic.
Actinobacteria-derived peptide antibiotics can be minimally classi-
fied into eight distinctive categories: lipopeptides, 2,5-diketopiper-
azines (DKPs), dimeric peptides, nucleosidyl peptides, thioamide-con-
taining peptides, thiopeptides, lasso peptides (also occasionally known
as lariat peptides), and typical cyclic peptides (Fig. 1). Lipopeptides
have linear or cyclic structures with a lipophilic fatty or aromatic acid
(FA or AA) hydrocarbon tail linked to the N-terminus of a short oligo-
peptide [52]. DKPs are the smallest cyclic peptides, as small as two
amino acids, with or without additional structural modifications. Di-
meric peptides are made up of two typical cyclic peptides by poly-
merization [64]. Nucleosidyl peptides are a family of closely related
compounds in structure: 3′-deoxy uridine is linked to the third amino

⁎
Corresponding author.
E-mail address: xueyun6688@163.com (Y. Xue).

https://doi.org/10.1016/j.peptides.2018.03.011
Received 17 January 2018; Received in revised form 16 March 2018; Accepted 18 March 2018
Available online 19 March 2018
0196-9781/ © 2018 Elsevier Inc. All rights reserved.
P. Zhao et al.
Table 1
The status of Actinobacteria-derived peptide antibiotic products in market and clinical trials.
Name Source
Viomycin Streptomyces puniceus
Capreomycin Streptomyces capreolus
Tuberactinomycin Streptomycin griseoverticillatus
Vancomycin Amycolatopsis orientalis
Teicoplanin Actinoplanes teichomyceticus
Daptomycin Streptomyces roseosporus
acid (N-methyl-2, 3-diaminobutyric acid) of the peptide skeleton
through 4′,5′-alkenamide [65]. Lipopeptides, DKPs, dimeric, and nu-
cleosidyl peptides are usually produced by nonribosomal peptide syn-
thetases, and normally contain a mixture of D and L amino acids.
Thiopeptides, also known as thiazolyl peptides, are highly modified
sulfur-rich peptides of ribosomal origin with thiazole, oxazole, or
thiazoline rings [66]. Similarly, lasso peptides are also ribosomally
synthesized and post-translationally modified peptides. The lasso scaf-
fold features an N-terminal 7–9 amino acid macrocycle followed by a C-
terminal linear portion of the peptide. In addition, the N-terminal
amino acid is either glycine or cysteine, while the amino acid that
closes the ring is either aspartic acid or glutamic acid [17,67]. In this
review, we provide a detailed overview of novel peptide antibiotic
products derived from Actinobacteria since the year 2000, with an em-
phasis on their structure and activity to highlight the potential as al-
ternatives to conventional antibiotics.
2. Cyclic lipopeptides containing piperazic or pipecolic acids
Piperazic/pipecolic acid motifs, the important structural units of
many microbial natural products, have been identified in an array of
architecturally complex cyclic lipopeptides and typical cyclic peptides
[68,69]. A total of 35 new cyclic lipopeptides containing these motifs
from Actinobacteria have been discovered since the year 2000 (Table 2).
Lydiamycins A–C, from soil-derived S. lydicus HKI0343 (deposited
as DSM16701 at the Deutsche Sammlung von Mikroorganismen und
Zellkulturen GmbH [DSMZ, Braunschweig, Germany]), have been
shown to selectively inhibit several Mycobacterium strains, such as M.
smegmatis, M. aurum, and M. vaccae, with minimum inhibitory con-
centrations (MICs) of 3.1–25.0 μg/mL [3]. Kutznerides 1–3 and 8, from
Kutzneria sp. 744 (GenBank accession no. DQ181633), which inhabit
the mycorrhizal roots of Piceaabies seedlings in forest nurseries, dis-
played moderate inhibition of some bacterial and fungal pathogens,
Peptides 103 (2018) 48–59
Molecular target Current Status References
Anti-tuberculosis Not marketed but widely used [53,54]
Anti-tuberculosis WHO recommended drugs [55]
Anti-tuberculosis WHO recommended drugs [56,57]
Methicillin-resistant Staphylococcus aureus WHO recommended drugs [58,59]
Gram-positive bacteria WHO recommended drugs [60,61]
Gram-positive bacteria FDA approval [62,63]
Fig. 1. General structural formula of Actinobacteria-
derived peptide antibiotics. (A) Lipopeptides. (B)
DKPs. (C) Dimeric peptides. (D) Nucleosidyl peptides.
(E) Thioamide-containing peptides. (F) Thiopeptides.
(G) Typical cyclic peptides. R1 = H, OH, or NH2; R2,
R3, R4, R5, R8, and R9 = functional groups (other than
amino and carboxyl) among peptide residues; R4 and
R5 = highly modified peptide chains; A1, A2, A4, and
A5 = the first, second, fourth, and fifth amino acid
residue, respectively.
Cylindrocladium canadense, Fusarium avenaceum, F. oxysporum, Nectriara
dicicola, Drechslera sorokinianaa, Erwinia carotovora, F. culmoruma, and
Staphylococcus aureus [27,70]. The most potent agents were tri-
chlorinated 2 and 8, with inhibition of the last two strains at 6 μM.
Svetamycins A, C, F, and G from Streptomyces sp. DSM14386 (deposited
at DSMZ) inhibited the growth of M. smegmatis and methicillin-resistant
S. aureus (MRSA) [71]. G showed the most potent activity against M.
smegmatis, with an 80% inhibitory concentration of 2 μg/mL. Pipala-
mycin, from soil-derived Streptomyces sp. ML297-90F8, showed activity
against S. aureus and Micrococcus luteus (with MICs of 0.1–0.2 μg/mL)
[72]. Oleamycins A and B, from root (Oleaceae europea) soil-derived
Streptomyces sp. Lv20-58 (deposited in the microorganism collection of
Ivan Franko Lviv National University, Lviv, Ukraine), displayed sig-
nificant activity against a panel of Gram-positive bacteria [73]. It is
noteworthy that MICs of 0.03–0.23 μg/mL against S. aureus and M. lu-
teus were observed.
Kettapeptin, from terrestrial Streptomyces sp. isolate GW99/1572,
exhibited much better inhibition against Bacillus subtilis, S. vir-
idochromogenes, S. aureus, and Escherichia coli than bacitracin A, with
diameters of inhibition zone (DIZs) of 12–20 mm at 5 μg/disk; the MIC
against B. subtilis was determined as 3.75 μg/mL [74]. Marformycins
A − F, from South China Sea-derived S. drozdowiczii SCSIO 10141
(GenBank acc. no. JX101493), showed selective antibacterial activity
against M. luteus (MICs = 0.06–4.0 μg/mL) [4]. Additionally, C and D
reportedly strongly inhibited the bacteria from the genus Propioni-
bacterium, particularly P. acnes and P. granulosum (MICs of 0.1–0.2 μg/
mL). Ulleungamide A, from soil-derived Streptomyces sp. KCB13F003
collected at Ulleung Island, displayed growth inhibition against S.
aureus and Salmonella typhimurium (DIZs = 9–17 mm at 25–50 μg/disk)
[69]. A mixture of friulimicins A–D, A–1437 A, B, E, and G, from soil-
derived A. Friuliensis HAG010964 collected at agarden entrance, were
active against S. aureus, M. luteus, and B. subtilis [28,75]. Glycinocins
A–D and laspartomycin C were isolated from terrestrial Actinomycete sp.
49
P. Zhao et al. Peptides 103 (2018) 48–59

Table 2
Cyclic lipopeptide products containing piperazic acids (Pip) or pipecolic acids (Pic) with antibiotic activities.

Name Sources Structural sequences Antibiotic activity MIC/DIZ/IC80 Ref

Lydiamycins A–C Terrestrial 1

PSA−5-ene-Pip-Ser*-Leu-Ala-Pip/4-Hy-Pip/5-ene-Pip* Antituberculotic a
3.1–25.0 μg/mL [3]
Kutznerides 1–3 and 8 Terrestrial 2
FA*-Pip/4-Cl-Pip-O-Me-Ser−3-Hy-Glu-3Trp deriv- Antibacterial and antifungal a
6–260 μM [27,70]
2-4MecP-Gly*
Svetamycins A, C, F, and G Unknown 5
FA*−3, 4-diHy-5-ene-Pip-Ala-4-Cl-Pip/4-Br-Pip-Pip/5,5- Antituberculotic and b
2–64 μg/mL [71]
diMe-Pip-2-Me-Ser* antibacterial
Pipalamycin Terrestrial 6
FA−3-Hy-Leu*-Pip-N-Hy-Ala-Gly-Pip-Ala* Antibacterial a
0.1–0.2 μg/mL [72]
Oleamycins A and B Terrestrial 7
FA−3-Hy-Leu*-Pip-Pip-Gly-N-Me-Gly-N-Me-Gly* Antibacterial a
0.03–0.23 μg/mL [73]
8 c
Kettapeptin Terrestrial FA−3-Hy-Leu*-Pip-N-Hy-O-Me-Ser-N-Me-Ala-Pip-Thr* Antibacterial 12–20 mm [74]
Marformycins A–F Marine 9
FA-Ile/Val-Thr*-O-Me-Tyr-Ile/Val-Pip/4-Hy-Pip-Leu-N- Antibacterial a
0.06–4.0 μg/mL [4]
Me-Val*
10 c
Ulleungamide A Terrestrial IPSA-N-Me-Phe-Thr*-Gly−4-Hy-Pic-Phe-Pic-2-ene-5-Hy- Antibacterial 9–17 mm [69]
6-Me-Pic*
11
Friulimicins A–D, A–1437 A, B, E, and Terrestrial FA-Asp/Asn-12Dab*-Pic−3-Me-Asp-Asp-Gly-Asp-Gly- Antibacterial ND [28,75]
G Dab-Val-Pro*
13
Glycinocins A–D and laspartomycin C Terrestrial FA-Asp-14Dap*-Pic-Gly-Asp-Gly-Asp-Gly-Thr-Ile/Val- Antibacterial ND [5,30]
Pro*

*denoting the linkage position of ring formation.

1
PSA: 2-pentylsuccinic acid.
2
FA:2-Hy-3,3-diMe-butyric acid.
3
Trp derive: 6,7-dichloro-3a-Hy- pyrrolidino[2,3-b]indole-2-carboxylic acid.
4
MecP: methylcyclopropyl.
5
FA: Hy-acetic acid.
6
FA: 2,2,3-Me-diHy-6-(3a-Me-butyl)-7-Et-tetrahydropyranyl propanoic acid.
7
FA: 2,2,3-Me-diHy-6-(2a-Me-butyl)/(2a-Me-propyl)-7-Et-tetrahydropyranyl propanoic acid.
8
FA: 2,2,3-Et-diHy-6-Me-7-(3a,5a-diMe-2a,6a-diene-octanone)-tetrahydropyranyl propanoic acid.
9
FA: formic acid.
10
IPSA: 2-isopropylsuccinic acid.
11
FA: △3-isotridecenoic acid, △3-isotetradecenoic acid, △3-anteisotridecenoic acid or △3-anteisopentadecenoic acid.
12
Dab: 2,3-diaminobutyric acid.
13
FA: 2-ene-12-Me- tridecanic acid, 2-ene-13-Me-tetradecanic acid, or 2-ene-14-Me-pentadecanic acid.
14
Dap: 2,3-diaminopropionic acid.
a
minimum inhibitory concentration (MIC).
b
80% inhibitory concentration (IC80).
c
the diameters of inhibition zone (DIZ); ND: not determined.

AW998 and S. viridochromogenes ATCC-29814 [5,30]. Among these, a
culture containing glycinocins A–D showed antibacterial activity
against S. aureus, while laspartomycin C, which has the same molecular
formula and general structure as glycinocin A, was active against
vancomycin-resistant S. aureus and MRSA.
3. Cyclic lipopeptides: aromatic, glyco- and bicyclic peptides
As shown in Table 3, another 34 special cyclic lipopeptides have
been reported since 2000, including eight aromatic peptides (e.g.,
turnagainolide C,NC-1, eudistamide B, skyllamycins A/RP-1776, B, and
C, and mohangamides A and B), five glycopeptides (mannopeptimycins
α–ε), and 21 bicyclic peptides (SW-163C and E, RK-1355A and B, sal-
inamide F, actinomycins G1/HKI-0155, G2, G3, G5,Y1–Y9, and Zp, and
RSP 01 and 02).
Turnagainolide C, from rhizosphere (Panaxnotoginseng) soil-derived
Streptomyces sp. S2236 preserved at the Yunnan Institute of
Microbiology, Yunnan University, China, showed moderate anti-
microbial activities against Candida albicans, E. coli, and S. aureus
(MICs = 32 μg/mL) [76]. NC-1, from red soil-derived Streptomyces
sp.FXJ1.172 (deposited as CGMCC 4.7312 in the China General Mi-
crobiological Culture Collection Center [CGMCC]), exhibited moderate
inhibitory effects against Mycobacterium bovis bacille Calmette-Guérin
(BCG; MIC = 44.4 μM) [77]. Eudistamide B, from marine invertebrate-
derived Streptomyces sp. WMMB 705, showed antibacterial activity
against MRSA, E. coli, and B. subtilis (MICs of 2.8–22.7 μM) [78]. Sky-
llamycins A (RP-1776), B, and C were isolated from soil-derived
Streptomyces sp. KY 11784 (deposited as FERM BP-5396 at the National
Institute of Bioscience and Human-Technology, Ibaraki, Japan), sandy
soil-derived Acta 2897 collected at a dune slack, and marine sediment-
derived strain 1675 (GenBank no. KF734086) collected at Westport
Jetty [79–81]. Of these, A exhibited weak activity against B. subtilis and
S. aureus. B and C had biofilm inhibition model activity against Pseu-
domonas aeruginosa with a half maximal effective concentration of
30–60 μM. Mohangamides A and B, from marine Streptomyces sp.
SNM55 collected in an intertidal mud flat, displayed inhibitory activity
against C. albicans isocitratelyase that is important in controlling mi-
crobial pathogens, with a 50% inhibitory concentration (IC50) of
4.4–20.5 μM [82]. However, they did not show significant antifungal
activity when the fungi were fed glucose. Interestingly, A inhibited C.
albicans grown on acetate, which indicates that the isocitratelyase is
crucial in the proliferation of the fungus on C2 substrates.
Mannopeptimycins α–ε, from S. hygroscopicus LL-AC98, were in-
hibitory against a diverse group of clinical isolates, such as methicillin-
susceptible S. aureus (MSSA), MRSA, methicillin-susceptible coagulase-
negative staphylococci, methicillin-resistant coagulase-negative staphy-
lococci, E. coli, Streptococcus, Enterococcus faecalis, and E. faecium [6,7].
Compound ε was the most active component against the first five of
these (MICs of 2–4 μg/mL), and had slightly lower efficacy than van-
comycin. SW-163C and E, from soil-derived Streptomyces sp. SNA15896,
had potent antimicrobial activities against an extensive range of or-
ganisms and were predominantly active against Xanthomonas oryzae, S.
aureus, B. subtilis, M. luteus, Mycohacterium phlei, Alternaria mali, and
Botryotinia fuckelianaat 50 μg/disk (DIZ values of 12–15 and 15–33 mm,
respectively for C and E) [83,84]. RK-1355A and B, from soil-derived
Streptomyces sp. RK88-1355, displayed moderate activities against S.
aureus, E. coli, and Magnaporthe oryzae (IC50 values of 0.02–3.6 μg/mL)
[85]. Salinamide F, from jellyfish (Cassiopea Xamachana)-derived
Streptomyces sp. CNB091 collected in the Florida Keys, exhibited anti-
bacterial activity against E. faecalis, S. aureus, Haemophilus influenza,
Neisseria gonorrhoeae, Enterobacter cloacae, and E. coli with a 50%
minimum inhibitory concentration of 0.2–100 μg/mL [86].

50
 P. Zhao et al.

Table 3
Cyclic lipopeptide products (aromatic, glycopeptides and bicyclic peptides) with antibiotic activities.

Name Sources Structural sequences Antibiotic activity MIC/EC50/IC50/DIZ/ Ref

MIC50

1 a
Turnagainolide C Terrestrial AA*-Val-Gly-Ile-Val* Antibacterial and antifungal 32 μg/mL [76]
2 a
NC-1 Terrestrial AA-Thr*-Ser-Gly-Asp-Ser*-Leu-Thr Antituberculotic 44.4 μM [77]
3 a
Eudistamide B Marine AA-Thr*-Phe-Leu-Tyr-Lys−3-Hy-Leu-Ser-Tyr-Tyr−3-Hy-Leu* Antibacterial 2.8–22.7 μM [78]
4 b
Skyllamycins A (RP-1776), B and C Terrestrial AA-Thr-Ala−3-Me-Asp/Asp-Gly−3-Hy-Phe-Pro−3-Hy-O-Me-Tyr-Trp-2-Hy-Gly-Leu−3-Hy- Antibacterial 30–140 μM [79–81]
Leu
5 c
Mohangamides A and B Marine AA-Thr*-N-Me−2-ene-Tyr-Leu-Phe-Thr-AsnSer-Thr/Ser (6FA)-N-Me−2-ene-Tyr/N-MeTyr- Antifungal 4.4–20.5 μM [82]
Leu-Phe-Thr-Asn-Ser*
7 a
Mannopeptimycins α–ε Man-Man-Tyr*/Tyr*/8FA-Man-Man-Tyr*-9Aiha-Aiha(N-Man)-Ser-Gly−3-Me-Phe* Antibacterial 2–128 μg/mL [6,7]
10 d
SW-163C and E Terrestrial AA-Ser*-Ala-N-Me-Cys**/N-Me−3-thioethyl-Ser**-N,2a-diMe-cyclopropyl-Gly-Ser(10AA)- Antibacterial and antifungal 12–33 mm [83,84]
Ala-N-Me-Cys**-N,2a-diMe-cyclopropyl-Gly*
10 c
RK-1355A and B Terrestrial AA-Ser*-Ala-N-Me−3-thiomethyl-Ser**/N-Me−3-thioethyl-Ser**-N,2a-diMe-cyclopropyl- Antibacterial and antifungal 0.02–3.6 μg/mL [85]
Gly-Ser(10AA)-N-Me-Cys sulfoxide-N,2a-diMe-cyclopropyl-Gly*
11 e
Salinamide F Marine FA-Thr*-Ile-4a-Hy-phenyl-Gly**-N-Me-Phe-Val−2-Hy-Gly*-Gly-12FA** Antibacterial 0.2–100 μg/mL [86]
d
Actinomycins G1(HKI-0155), G2, G3, G5,Y1–Y9, Terrestrial α-ring: 13AA-Thr*-Val-Pro/3-Hy−5-Me-Pro/5-Me-Pro-14Sar- N-Me-Val* Antibacterial, antifungal, and 8–45 mm [8,87–90]
Zp, RSP 01 and 02 antituberculotic
a
β-ring: 13AA−4-Hy-Thr*/4-Cl-Thr*/Thr*-Val-3-Hy-5-Me-Pro/Pro/3-Hy-Pro/4-O-Pro/5-Me- .002–9.57 μg/mL
Pro/4-Hy-Pro-Sar-N-Me-Val*/Ala*AA−4-Hy-Thr*/4-Cl-Thr*/Thr*-Val-3-Hy-5-Me-Pro/Pro/3-

51
Hy-Pro/4-O-Pro/5-Me-Pro/4-Hy-Pro-Sar-N-Me-Val*/Ala*

*, **: denoting the linkage position of the first and second ring formation.
1
AA: aromatic acid, 3-Hy-5-phenylpent-4-enoic acid (Hppa).
2
AA: ortho-2-(1-Hy-n-pentyl)-epoxy ethyl-cinnamic acid.
3
AA: ortho-Me-cinnamic acid.
4
AA: ortho-1- propenyl-cinnamic acid.
5
AA: ortho-1-pentenyl-cinnamic acid.
6
FA: 3-ene-3-(4-pentenyl)-dihydropyridyl-propionic acid.
7
Man: mannose.
8
FA: 3-Me-butyric acid.
9
Aiha: 3-(2-amino-imidazolidyl)-Hy-Ala.
10
AA: 3-Hy-quinaldic acid.
11
FA: 2, 4-diMe-3-Hy-pentanoic acid.
12
FA: 4, 5-diHy-4-hydroxymethyl-2-ene-hexanoic acid.
13
AA: 2-amino-4,6-dimethylphenoxazine-3-one-1,9-dicarboxylic acid.
14
Sar: sarcosine.
a
MIC.
b
half maximal effective concentration (EC50).
c
50% inhibitory concentration (IC50).
d
DIZ.
e
50% minimum inhibitory concentration (MIC50).
Peptides 103 (2018) 48–59
P. Zhao et al. Peptides 103 (2018) 48–59

Actinomycins G1 (HKI-0155), G2, G3, G5, Y1–Y9, and Zp, and RSP 01
and 02 were isolated from Streptomyces sp. HKI-0155, rhizosphere (Ci-
trussinensis) S. iakyrus DSM 41873 (on deposit in DSMZ), soil-derived
Streptomyces sp. Gö-GS12, and soil-derived Streptomyces sp. RAB12
collected from the rhizosphere of Wedelia trilobata (deposited in The
Microbial Type Culture Collection and Gene Bank, Chandigarh, India,
with accession no. MTCC 12747) [8,87–90]. Of these, G1 displayed
weak activity against B. subtilis. G2, G3, and G5, and Y1–Y5 exhibited
significant activity against E. coli, S. aureus, and B. subtilis (DIZ values of
8–45 mm at 50 μg/disk). In particular, G2 and Y1 had slightly lower
efficacy than actinomycin D. It has also been reported that Y1, Y3, Y4,
Y6–Y9, and Zp showed potent inhibition against common Gram-posi-
tive, Gram-negative, and fungal strains, such as S. aureus, M. luteus, B.
subtilis, M. aurum, E. coli, and Saccharomyces cerevisae (MIC values of
0.002–9.57 μg/mL). Interestingly, Y1, Y8, Y9, and Zp had the highest
antibacterial activity. In addition, RSP 01 and 02 were highly effective
against P. aeruginosa, M. luteus, S. aureus, S. typhimurium, B. subtilis, and
C. albicans with DIZs, MICs, and minimum bactericidal concentrations
of 14–40 mm at 100 μg/disk, 0.007–0.125, and 0.007–0.250 μg/mL,
respectively, which were more potent than actinomycin D.
4. Other cyclic lipopeptides
In addition to the four categories described earlier, since the year
2000, 44 novel antibiotic peptide products from other categories have
been reported (Table 4). Hangtaimycin, from soil-derived S. spectabilis
CPCC 200148, generated a small growth inhibition zone inoculated
with B. subtilis and C. albicans at 100–800 μg/disk [9]. Tumescenamide
C, from soil-derived Streptomyces sp. KUSC_F05, exhibited a growth
inhibitory zone with high selectivity against Streptomyces species in-
cluding S. coelicolor, S. lividans, and Streptomyces sp. at 3–30 μg/disk
[91]. Arylomycins A1–A6 and B1–B7, from soil-derived Streptomyces
sp.Tü 6075 collected from a tropical rain forest and S. parvus
HCCB10043 (documented as CGMCC 4027 in CGMCC), exhibited an-
tibiotic activities against Gram-positive bacteria and the fungus Mucor
hiemalis [10,92,93]. Among them, Rhodococcus erythropolis, S. vir-
idochromogenes, Brevibacillus brevis and Staphylococcus epidermidis were
the most sensitive (MIC and DIZ values < 30 μg/mL and 15–26 mm,
respectively). Peptidolipins B and E, from ascidian (Trididemnumor bi-
culatum)-derived Nocardia sp.WMMB215 (GenBank no. JN638997),
demonstrated weak activity against MRSA and MSSA (MICs = 64 μg/
mL) [31]. Hormaomycins B and C, from marine mudflat-derived
Streptomyces sp. SNM55 (GenBank no. KP133063), displayed potent
activity against Kocuria rhizophila, S. aureus, and Streptococcus pyogenes
(MIC values of 0.23–14 μM), but showed moderate activities against B.
subtilis, Salmonella enterica, and Proteus hauseri [94]. Fijimycins A–C,
from marine sediment-derived Streptomyces sp. CNS-575 (GenBank no.
GQ325662), were shown to possess appreciable activity against three

Table 4
Other cyclic lipopeptide products with antibiotic activities.

Name Sources Structural sequences Antibiotic activity MIC/DIZ/IC50 Ref

1
Hangtaimycin Terrestrial LFA−2-ene-Ala-O-Me-Thr−2-ene-2Abu*-N-Me-Trp* Antibacterial and ND [9]
antifungal
3
Tumescenamide C Terrestrial FA-Thr*-Leu-Val-Tyr−2-ene-Abu* Antibacterial ND [91]
Arylomycins A1–A6 and Terrestrial 4
FA-N-Me-Ser-Ala-Gly–N-Me-5Hpg*-Ala-Tyr/nitro-Tyr* Antibacterial and a
1–100 μg/mL [10,92,93]
B1–B7 antifungal
b
15–26 mm
Peptidolipins B and E Marine 6
FA-Thr*-Val-Ala-Pro-Ile-Val-O-Me-Thr* Antibacterial a
64 μg/mL [31]
Hormaomycins B and C Marine 7
FA−3-8Ncp-Ala-Thr*-Phe/3-Me-Phe−3-Ncp-Ala-Phe/3-Me-Phe-Ile- Antibacterial a
0.23–14 μM [94]
4-9Pe-Pro*
Fijimycins A–C Marine 10
FA-Thr*-Leu−4-Hy-Pro-Sar-N,3-diMe-Leu-Ala/Ser-2-FA-Thr*- Antibacterial a
4–32 μg/mL [95]
Leu−4-Hy-Pro-Sar-N,3-diMe-Leu-Ala/Ser-2-11Ph-Sar/N-Me-Leu*
Enduspeptides A–F Terrestrial 12
FA-Thr*-Phe-Leu-Val-Pro-Pro-Leu/Phe-N-Me-Tyr/Phe* Antifungal c
1.72–45.38 μg/mL [96]
Octaminomycins A and B Terrestrial 13
FA-Thr*-Phe-Leu-Val-Pro-Leu-N-Me-Tyr-Pro* Anti-plasmodial c
0.8–1.6 μM [97]
Taromycins A and B Terrestrial 14
FA−6-Cl-Trp-Asn-Asp-Thr*-Gly-15Orn-Asp-Ala-Asp-Gly-Ala-3-Me- Antibacterial a
6–100 μM [11,98]
Glu-4Cl-16Kyn*
a
3.1–12.5 μg/mL
A21978C1–3 Terrestrial 17
FA-Trp-Asn-Asp-Thr-Gly-Orn-Asp-Ala-Asp-Gly-Asn−3-Me-Glu-Kyn Antibacterial a
0.15–0.6 μM [12]
A54145D derivatives Terrestrial 18
FA-Trp-Glu-Asn/Hy-Asn-Thr-Sar-Ala-Asp-Lys-Asp/Hy-Asp/O-Me-Asp- Antibacterial a
1–32 μg/mL [13]
Gly-Asn−3-Me-Glu/Glu-Ile

*denoting the linkage position of the ring formation.

ND: not determined.
1
LFA: the linear fatty acid chain comprising 2,4-hexadienoic acid and 2-methyl-2-ene-4-amino-pentanoic acid linked by amide bond.
2
Abu: 2-Aminobutyric acid.
3
FA: 2,4-diMe-heptanoic acids.
4
FA: the saturated isoC11, C12, C13, C14, n-C12, anteiso-C13 or C15 fatty acid.
5
Hpg: 4-hydroxyphenylglycyl.
6
FA: the saturated 3-Hy-C26 or 3-Hy-19-ene-C28 fatty acid.
7
FA: 1a-chloro-N-Hy-pyrrol-carboxylic acid (Chpca).
8
Ncp: 2-nitro-cyclopropyl.
9
Pe: propenyl.
10
FA: 2-Hy-picolinic acid.
11
Ph: phenyl.
12
FA: acetic, propionic, butyric or 3-Me-butyric acid.
13
FA: acetic or 3-Me-butyric acid.
14
FA: 2,4-diene-C8 or 2,4-diene-6-Me-C8 fatty acid.
15
Orn: Ornithine.
16
Kyn: Kynurenine.
17
FA: anteiso-C11, isoC12 or anteiso-C13 fatty acid.
18
FA: anteiso-C11 fatty acid.
a
MIC.
b
IC50.
c
DIZ.

52
P. Zhao et al. Peptides 103 (2018) 48–59

MRSA strains: ATCC33591, Sanger 252, and UAMS1182 (MIC values of
4–32 μg/mL) [95]. Enduspeptides A–F, from soil-derived Streptomyces
sp. strain collected from a coal mine, were found to have antifungal
abilities against Candida glabrata [94]. In particular, A–C exhibited the
most potent activity (IC50 values of 1.72–8.13 μg/mL). Octaminomycins
A and B, from soil-derived Streptomyces sp. RK85-270 (GenBank no.
KY039979), showed good activity against three chloroquine-sensitive
and −resistant strains of Plasmodium falciparum: 3D7, Dd2, and K1
(IC50 values of 0.8–1.6 μM) [97].
Moreover, 14 daptomycin analogues were isolated from S. coelicolor
M1146/pCAP01-tarM1, M1146-M1, recombinant S. roseosporus KN362,
and S. fradiae A54145. In antibiotic assays, taromycins A and B had
moderate bioactivity against MRSA, vancomycin-resistant Enterococcus
(VRE), and E. faecalis (MICs of 6–100 μM or 3.1–12.5 μg/mL) at a 50 μg/
mL calcium [11,98]. A21978C1–3 exhibited potent inhibitory activity
against S. aureus (MICs of 0.15–0.6 μM), which was essentially
equivalent or superior to daptomycin [12]. Nine A54145D derivatives
had MICs of 1–32 μg/mL against S. aureus [13].
5. Linear lipopeptides, DKPs, and dimeric and nucleosidyl
peptides
As shown in Table 5, the linear lipopeptide brevifactin, from the
marine sponge Dendrilla nigra-derived B. aureum MSA13 (GenBank no.
GQ153943), showed a broad spectrum of activity against human pa-
thogens such as C. albicans, E. coli, Proteus mirabilis, hemolytic Strepto-
coccussp., P. aeruginosa, M. luteus, S. epidermidis, E. faecalis, Klebsiella
pneumoniae, Bacillus sp., and S. aureus (DIZ values of 11–27 mm at 5 μg/
disk) [32]. Lipid-peptide (−)-1, from various Streptomyces species, ex-
hibited significant in vitro activity against P. falciparum (IC50 = 0.8 μM)
[99]. WS9326D, from Streptomyces sp. 9078, efficiently killed the adult
Brugia malayi parasite at concentrations as low as 10 nM, representing
another lead scaffold for antifilarial drug discovery [100]. Madur-
astatins A1 and C1 (MBJ-0034), from pathogenic A. madurae IFM 0745
(from a Japanese patient with bronchitis) and deep sea sediment-de-
rived Actinomadura sp. DEM31376, showed growth inhibition against
M. luteus and B. subtilis, presumably through an inhibition of Fe3+
uptake [33,34].
The DKP derivative (3Z,6S)-3-benzylidene-6-isobutylpiperazine-2,5-
dione was first produced by S. albulus KO-23, but its antibiotic activity
was not reported [14]. Afterwards, both the former and (3Z,6Z)-3-(4-
hydroxybenzylidene)-6-isobutylidenepiperazine-2,5-dione were iso-
lated from coastal sediment-derived Streptomyces sp. FXJ7.328 (Gen-
Bank no. JF346514) collected at Huanghai beach [101]. They displayed
modest antiviral activity against the influenza A (H1N1) virus (IC50
values of 28.9–41.5 μM). Pyrocoll, from steel waste tip soil-derived and

Table 5
Linear lipopeptide, DKPs, dimeric, nucleosidyl, and thioamide-containing peptide products with antibiotic activities.

Name Sources Structural sequences Antibiotic activity DIZ/IC50/MBC/MIC Ref

0 a
Brevifactin Marine FA-Gly-Gly-Leu-Pro Antibacterial and antifungal 11–27 mm [32]
Lipid-peptide (−)-1 Unknown 1
FA−3-Hy-Me-Asp-4-ene-Ile-Asp Anti-plasmodial b
0.8 μM [99]
2 c
WS9326D Unknown AA-Thr-N-Me−2-ene-Tyr-Leu-Phe-Thr Anti-brugia 10 nM [100]
Madurastatins A1 and C1 (MBJ-0034) Terrestrial 3
AA/AA derive −4Ser derive-Ala/Gly-β-Ala- Antibacterial ND [33,34]
N’-Me-N-Hy-Orn-N-Hy-5Orn derive
(3Z,6S)-3-benzylidene-6- Marine Cyclo (2-ene-Tyr-2-ene-Leu) Antiviral b
28.9–41.5 μM [14,101]
isobutylpiperazine-2,5-dione
(3Z,6Z)-3-(4-h-benzylidene)-6- Marine Cyclo (2-ene-Phe-Leu)
isobutylidenepiperazine-2,5-dione
a
Pyrocoll Terrestrial Cyclo (Pro-Pro) Antibacterial, antifungal, anti- 9–21 mm [102]
plasmodial, and anti-
trypanosomal
d
1–10 μg/mL
Sch 725148 Unknown Cyclo (N-Me-Trp-N-Me-Trp) Antifungal d
32 μg/mL [35]
Iso-naseseazine B and naseseazines C Marine Cyclo (Pro-Trp)-Cyclo (6Trp derive-Pro) Antifungal and anti-plasmodial b
3.52 μM [103,104]
Chloptosin Terrestrial α-ring: 6-Cl-Trp derive*-Val-Pip-Pip-O-Me- Antibacterial d
0.025–1.56 μg/mL [105]
Ser-Thr*
β-ring: 6-Cl-Trp derive*-Val-Pip-Pip-O-Me-Ser-
Thr*
Sansanmycins A–C and F Terrestrial Uracil-Sugar-7AMBA (meta-Tyr/8TIC)-Met/ Antituberculotic and antibacterial d
8–20 μg/mL [106–108]
Leu/Met sulfoxide-Trp/meta-Tyr
Thioholgamides A and B Unknown Val*-Ala-Phe-N,N’-diMe−3-Hy-9Hhis-10avi- Antituberculotic and antibacterial d
4–32 μg/mL [15]
Me-Cys*-Ala-11Ala’-Ala’-Ala-12Met’/Met’
sulfoxide-13Val’-pyruvate

*denoting the linkage position of the ring formation.

ND: not determined.
0
FA: C18 saturated fatty acid.
1
FA: 3-ene-5-Me-C10 fatty acid.
2
AA: ortho-1-butenyl cinnamic acid.
3
AA/AA derive: salicylic acid/N-terminal 2-(2-hydroxyphenyl)oxazoline.
4
Ser derive: aziridine methanoic acid for A1 or oxazoline methanoic acid for C1 (MBJ-0034).
5
Orn derive: the lactam formed at Orn of the C-terminus.
6
Trp derive: 3a-Hy-2,3,3a,8a–hexahydropyrrolo [2,3-b]indole-2-carboxylic acid.
7
AMBA: 2-amino-3-methylaminobutyric acid.
8
TIC: 1,1-diMe-6-Hy-1,2,3,4-tetradhydro- 3-isoquinoline carboxylic acid.
9
Hhis: homo-histdine.
10
avi: 2-aminovinyl.
11
Ala’.
12
Met’.
13
Val’: denoting the C]O bond replaced by C = S in the corresponding amino acids Ala, Met, and Val, respectively.
a
DIZ.
b
IC50.
c
minimum bactericidal concentrations (MBC).
d
MIC.

53
P. Zhao et al. Peptides 103 (2018) 48–59

alkaliphilic Streptomyces sp. AK (deposited in the culture collection of
the University of Newcastle), showed activity against various Ar-
throbacter strains and filamentous fungi like Botrytis cinerea, Aspergillus
viridinutans, and Paecilomyces variotii (DIZ values of 9–21 mm at 20 μg/
disk; MICs of 1–10 μg/mL) [102]. Furthermore, it also exhibited mod-
erate activity against P. falciparum, Trypanosoma cruzi, and T. brucei
rhodesiense (IC50 values of 1.19–17.6 μg/mL). Sch 725148, from Mi-
cromonospora sp., was effective against Saccharomyces cerevisiae
(MIC = 32 μg/mL) [35]. Dimeric DKPs iso-naseseazine B and nasesea-
zine C were isolated from Yellow Sea sediment-derived Streptomyces sp.
SMA-1 and marine sediment-derived strain USC-636 (GenBank no.
KX379154) obtained from the Sunshine Coast [103,104]. For the
former, minor antifungal activity against fluconazole-resistant C. albi-
cans has been reported, while naseseazine C displayed moderate anti-
plasmodial activity against P. falciparum (IC50 = 3.52 μM).
The dimeric peptide chloptosin, from soil-derived Streptomyces sp.
MK498-98F14 (deposited in the National Institute of Bioscience [FERM
P-16200] and Human-Technology Agency of Industrial Science and
Technology [FERM BP-6874]), strongly inhibited the growth of Gram-
positive bacteria, such as Staphylococcus, Micrococcus, Bacillus, and
MRSA (MICs of 0.025–1.56 μg/mL) [105]. Nucleosidyl-peptide anti-
biotics sansanmycins A–C and F are produced by soil-derived Strepto-
myces sp. SS [106–108]. The former three were effective against My-
cobacterium tuberculosis and P. aeruginosa (MICs of 8–20 μg/mL), while F
only showed inhibitory activity against P. aeruginosa. Thioamide-con-
taining peptide products thioholgamides A and B, from S. malaysiense
MUSC 136 57 (DSM 100712), showed moderate inhibitory activity
against Gram-positive bacteria and were particularly active against M.
smegmatis (MIC values of 1–2 μg/mL) [15].
6. Thiopeptides
To date, 25 new thiopeptides have been reported (Table 6).The
linear goadsporin, from soil-derived Streptomyces sp. TP-A0584, showed
significant growth inhibition against S. lividans, S. coelicolor, and
Streptomyces scabies (MICs of 0.2–6.4 μg/mL) [109,110]. Nocathiacins
I–III, thiazomycin, and thiazomycins A–D were identified in a culture of
soil-derived Nocardia sp. WW-12651 (also renamed Amycolatopsis fas-
tidiosa; GenBank no. EU072442; deposited both in the American Type
Culture Collection [ATCC] with accession no. ATCC 202099 and the
Merck culture collection with accession no. MA7332) [36,37,111–114].
Among them, the former three exhibited potent activity against a wide
spectrum of Gram-positive bacteria, including Streptococcus pneumo-
niae, penicillin-resistant S. pneumoniae, S. pyogenes, E. faecalis, multi-
drug resistant E. faecium, Enterococcus avium, S. aureus, MRSA, S. epi-
dermidis, Streptococcus haemolyticus, and Moraxella catarrhalis (MICs of
0.001–0.25 μg/mL). Thiazomycin and thiazomycin A had similar
growth inhibition of S. aureus, MRSA, multi-drug resistant S. aureus, S.
haemolyticus, S. epidermidis, E. faecalis, multi-drug resistant E. faecium,
S. pneumoniae, penicillin-resistant S. pneumoniae, and S. pyogenes (MIC
values of 0.003–0.03 μg/mL), while thiazomycins B–D were generally
less active (MICs of 0.004–0.25 μg/mL). Interestingly, all of them
showed more potent activity than linezolid and erythromycin. The
cyclic cyclothiazomycin B1, from Streptomyces sp. A307 and soil-de-
rived strain HA 125-40, strongly inhibited the growth of several fila-
mentous fungal strains including Mucor mucedon, M. javanicus, F. oxy-
sporum, F. solani, F. sporotrichioides, F. avenaceum, Gibberell azeae, G.
fujikuroi, and Penicillium chrysogenum (MIC values of 0.063–0.63 μg/mL
or 0.02–0.41 μM) [115,116].
Val-geninthiocin, from soil-derived Streptomyces sp. RSF18
(GenBank no. EU294139) collected from a rose field, showed minor
activity against B. subtilis, S. aureus, S. viridochromogenes, Mucor miehei,
and C. albicans (DIZs of 11–14 mm) [117]. Philipimycin, from soil-de-
rived A. philippinensis MA7347 (ATCC PTA 7551) associated with the
rhizosphere of a specimen of Dinteranthus microspermus, exhibited po-
tent growth inhibitory activities against Gram-positive bacteria, such as
S. aureus, MRSA, S. aureus (ThiazR), S. pneumoniae, S. pyogenes, E. fae-
calis, and E. faecium (MICs ≦ 0.5 μg/mL) [29]. Thiomuracins A–I, from
Nonomuraea sp. Bp3714-39, had modest activity against E. faecalis and
S. aureus (MICs of 0.25–16 μg/mL) [39]. Nocardithiocin, from patho-
genic N. pseudobrasiliensis IFM 0757 obtained from a patient at the
Health Center, University of Texas, showed a strong antimicrobial ac-
tivity against Gordonia bronchialis, Corynebacterium xerosis, M. smeg-
matis, Nocardia asteroids, Mycobacterium intracellulare, as well as mul-
tiple rifampicin-susceptible and −resistant M. tuberculosis strains (MICs
of 0.0078–6.25 μg/mL) [118]. TP-1161, from marine sediment-derived
Nocardiopsis sp. TFS65-07, inhibited the growth of Gram-positive
strains, including VRE, S. aureus, S. haemolyticus, S. epidermidis, S.
pneumonia, and Streptococcus B (MICs of 0.25–4.0 μg/mL), which was
comparable to or lower than that of vancomycin [41]. Marthiapeptide
A, from marine sediment-derived M. thermotolerans SCSIO 00652 col-
lected in the northern South China Sea, exhibited antibacterial activity
against M. luteus, S. aureus, B. subtilis, and B. thuringiensis (MICs of
2.0–8.0 μg/mL) [43]. Globimycin, from soil-derived S. globisporus NRRL
B-2709, showed significant inhibition of Gram-positive bacteria in-
cluding B. subtilis, S. aureus, and M. luteus (MICs of 0.25–1.0 μg/mL)
[26].
7. Lasso peptides
Nine novel lasso peptides have been recently identified (Table 7).
Achromosin, from S. achromogenes NBRC12735T (preserved in the NITE
Biological Resource Center [NBRC, Japan]), only showed inhibitory
activity against M. luteus (DIZ = 11 mm at 10 μg/disk) [16]. Chax-
apeptin, from Hyperarid Atacama Desert soil-derived S. leeuwenhoekii
C58, was found to have moderate effects against S. aureus and B. subtilis

Table 6
Thiopeptide products with antibiotic activities.

Name Class Sources Antibiotic activity MIC/DIZ Ref

Goadsporin Linear Terrestrial Antibacterial a

0.2–6.4 μg/mL [109,110]
Nocathiacins I–III Cyclic Terrestrial Antibacterial a
0.001–0.25 μg/mL [36,111]
Thiazomycin and thiazomycins A–D Terrestrial Antibacterial a
0.003–0.25 μg/mL [37,112–114]
Cyclothiazomycin B1 Terrestrial Antifungal a
0.063–0.63 μg/mL [115,116]
a
0.02–0.41 μM
b
Val-geninthiocin Terrestrial Antibacterial and antifungal 11–14 mm [117]
Philipimycin Terrestrial Antibacterial a
≦0.5 μg/mL [29]
Thiomuracins A–I Unknown Antibacterial a
0.25–16 μg/mL [39]
Nocardithiocin Terrestrial Antibacterial a
0.0078–6.25 μg/mL [118]
TP-1161 Marine Antibacterial a
0.25–4.0 μg/mL [41]
Marthiapeptide A Marine Antibacterial a
2.0–8.0 μg/mL [43]
Globimycin Terrestrial Antibacterial a
0.25–1.0 μg/mL [26]

a
MIC.
b
DIZ.

54
P. Zhao et al. Peptides 103 (2018) 48–59

Table 7
Lasso peptide products with antibiotic activities.

Name Sources Structural sequences Antibiotic activity DIZ/MIC Ref

a
Achromosin Unknown Gly*-Ile-Gly-Ser-Gln-Thr-Trp-Asp*- Antibacterial 11 mm [16]
Thr-Ile-Trp-Leu-Trp-Asp
Chaxapeptin Terrestrial Gly*-Phe-Gly-Ser-Lys-Pro-Leu-Asp*- Antibacterial b
30–35 μg/mL [17]
Ser-Phe-Gly-Leu-Asn-Phe-Phe
Lariatin A Terrestrial Gly*-Ser-Gln-Leu-Val-Tyr-Arg-Glu*- Antituberculotic b
3.13–6.25 μg/mL [44,45]
a
Trp-Val-Gly-His-Ser-Asn-Val-Ile-Lys-Pro 18–19 mm
Lariatin B Terrestrial Gly*-Ser-Gln-Leu-Val-Tyr-Arg-Glu*-
Trp-Val-Gly-His-Ser-Asn-Val-Ile-Lys-Gly-Pro-Pro
Lassomycin Terrestrial Gly*-Leu-Arg-Arg-Leu-Phe-Ala-Asp*-Gln-Leu-Val-Gly-Arg-Arg-Asn-Ile-CO 2- Antituberculotic and b
0.1–3.1 μg/mL [46]
Me antibacterial
b
0.07–1.65 μM
a
Actinokineosin Unknown Gly*-Tyr-Pro-Phe-Trp-Asp-Asn-Arg-Asp*-Ile-Phe-Gly-Gly-Tyr-Thr-Phe-Ile-Gly Antibacterial 8–8.5 mm [47]
Sphaericin Unknown Gly*-Leu-Pro-Ile-Gly-Trp-Trp-Ile-Glu*-Arg-Pro-Ser-Gly-Trp-Tyr-Phe-Pro-Ile [48]
Sviceucin Unknown Cys*+-Val-Trp-Gly-Gly-Asp-Cys**-Thr-Asp+-Phe-Leu-Gly-Cys*-Gly-Thr-Ala- Antibacterial b
1.25–2.5 μM [18]
Trp-Ile-Cys**-Val
Streptomonomicin Unknown Ser*-Leu-Gly-Ser-Ser-Pro-Tyr-Asn-Asp*-Ile-Leu-Gly-Tyr-Pro-Ala-Leu-Ile-Val- Antibacterial b
4–128 μg/mL [49]
Ile-Tyr-Pro
b
2–57 μM

*, **, : denoting the linkage position of the first, second and third ring formation, respectively.
+

a
DIZ.
b
MIC.

(MICs of 30–35 μg/mL) [17]. Lariatins A and B, from soil-derived
Rhodococcus jostii. K01-B0171 (DDBJ accession no. AB204817), showed
selective activity against M. smegmatis (MICs of 3.13–6.25 μg/mL; DIZs
of 18–19 mm at 10 μg/disk) [44,45]. Lassomycin, from soil-derived L.
kentuckyensis IS009804 (GenBank no. DQ291145) had low MICs of
0.1–3.1 μg/mL or 0.07–1.65 μM, against a variety of M. tuberculosis
strains (including susceptible, multi-drug resistant, and extremely drug
resistant isolates), M. avium, and M. smegmatis [46]. It has also been
reported that this compound was less active against other actino-
bacteria like P. acnes and Bifidobacterium longum. Actinokineosin and
sphaericin were isolated from A. spheciospongiae DSM45935T (DSMZ)
and P. sphaerica JCM 9374T (the Japan Collection of Microorganisms,
JCM), respectively. Both of them exhibited inhibitory zones against M.
luteus (DIZs of 8–8.5 mm at 50 μg/disk) [47,48]. Sviceucin, from S.
sviceus DSM 924, displayed strong activity against Bacillus megaterium,
Lactobacillus bulgaricus, S. aureus, L. sakei, and a closely related Strep-
tomyces (MICs of 1.25–2.5 μM) [18]. Streptomonomicin, from S. alba
YIM 90003, inhibited the growth of Bacillus anthracis, B. halodurans, B.
cereus, B. subtilis, Listeria monocytogenes, E. faecalis, and S. aureus (MICs
of 4–128 μg/mL or 2–57 μM) [49].
8. Typical cyclic peptides
The 34 newly discovered typical cyclic peptides are shown in
Table 8. Glomecidin, from soil-derived S. lavendulae H698 SY2, ex-
hibited growth inhibitory activity against Glomerellacin gulata, Colleto-
trichum gloeosporioides, and C. agenarium (MICs of 0.78–1.56 μg/mL)
[19]. NW-G01, 03, and 06–12, from soil-derived S. alboflavus 313
(GenBank no. FJ032029) collected from Qinling Mountain, could ef-
fectively inhibit Gram-positive bacteria, such as B. cereus, B. subtilis, S.
aureus, and MRSA (MICs of 1.56–25 μg/mL) [20,21,119–123]. Of them,
the most sensitive agents were NW-G01, 06, 08, 10, and 12. No-
cardiamides A and B, from marine sediment-derived Nocardiopsis sp.
CNX037, showed negligible antimicrobial activities against the seven
indicator strains, E. coli, S. aureus, E. faecalis, Bacillus thuringensis, B.
subtilis, M. luteus, and C. albicans [42]. Desotamides B, E, and F, and
wollamides A and B were isolated from semiarid terrain soil-derived
Streptomyces sp. MST-115088 or deep-sea sediment-derived S. scopulir-
idus SCSIO ZJ46 (GenBank no. KJ784514, preserved at CGMCC
[CGMCC no. 7862]). Desotamide B displayed moderate activities
against S. pneumoniae, methicillin-resistant S. epidermidis, and S. aureus
(MICs of 12.5–32 μg/mL) [22,124]. It has also been reported that all of
these peptides exhibited significant growth inhibitory activity against
B. subtilis (IC50 = 1.0–5.2 μM), with only desotamide F and wollamide B
effective against S. aureus (IC50 = 0.6–6.8 μM). Specifically, the last two
peptides inhibited the growth of M. bovis, BCG (IC50 = 2.8–3.1 μM).
Pargamicins A–D, from soil-derived Amycolatopsis sp. ML1-hF4 col-
lected at Shinagawa, showed different activities against several strains
of Gram-positive bacteria, such as M. luteus, B. subtilis, B. cereus, Cor-
ynebacterium bovis, S. aureus, MRSA, multi-drug resistant S. aureus, E.
faecalis/faecium, and VRE (MICs of 0.4–64 μg/mL) [38,125]. Interest-
ingly, A and C were the most effective inhibitors, on par with vanco-
mycin.
Curacomycin, from S. curacoi NBRC 12761T (deposited at the NBRC
culture collection), exhibited antimicrobial activity against B. subtilis, S.
aureus, M. luteus, and P. aeruginosa (DIZ values of 9–15 mm) [23]. Ul-
leungmycins A and B (Nicrophorusamide A), from Streptomyces sp.
KCB13F003 and Microbacterium sp. UTG9 (GenBank no. MF000987;
from the gut of the carrion beetle Nicrophorus concolor), were active
against multiple strains of Gram-positive bacteria including MRSA,
quinolone-resistant S. aureus, B. subtilis, S. pneumoniae, E. faecalis, S.
aureus, E. faecium, and S. enteric (MICs of 8–32 μg/mL) [50,126].
Thermoactinoamide A, from the thermophilic bacterium T. vulgaris
ISCAR 2354 collected at a coastal hydrothermal vent in Iceland, in-
hibited the growth of S. aureus (MIC = 35 μM) [51]. Streptocidins A–D,
from soil-derived Streptomyces sp. Tü607 collected at Cape Coast,
showed antibiotic activities against Arthrobacter aurescens, B. subtilis, S.
aureus, and Streptomyces (MICs of 1–10 μg/mL; DIZs of 6–10 mm)
[127,128]. Ambobactin, from root (Platycladus orientalis)-derived S.
ambofaciens F3 (GenBank no. KT368940), exhibited strong activity
against B. subtilis, E. coli, E. carotovora, Pseudomonas syringae, Ralstonia
solanacearum, X. oryzae, B. cereus,and S. aureus (MICs of 1.56–6.25 μg/
mL) [24]. Telomycin 2, from S. canus ATCC 12646, showed good an-
tibiotic activities against S. aureus and MRSA (MICs of 4 μg/mL) [25].
Ohmyungsamycins A and B were isolated from sediment-derived
Streptomyces sp. SNJ042 collected from Shinyang Beach (deposited in
the Korea Collection for Type Cultures [no. KCTC18240P]) [129]. In-
terestingly, A displayed significant inhibitory activity against B. subtilis,
Kocuria rhizophila, and P. hauseri (MICs of 1.07–4.28 μM), while B was
less active. Ecumicin, from soil-derived Nonomuraea sp. MJM5123, was
potently active against M. tuberculosis (MIC = 0.26 μg/mL) [48].

55
 P. Zhao et al.

Table 8
Typical cyclic peptides with antibiotic activities.

Name Sources Structural sequences Antibiotic activity MIC/IC50/DIZ Ref

a
Glomecidin Terrestrial 4,5-diHy-Pip*-O-Me-Tyr-Ile-His* Antifungal 0.78–1.56 μg/mL [19]
a
NW-G01,03,06-12 Terrestrial 6-Cl-Trp drive*/5-Me-Trp drive*/Trp drive*- Val/Leu-Pip/5-ene-Pip-Pip/4-O-Me-5-ene-Pip/4-O- Antibacterial 1.56–25 μg/mL [20,21,119–123]
Me-3,5-diene-Pip-N-Me-Ala/Ala-Pip*
Nocardiamides A and B Marine Leu*-Val-Val-Val-Tyr-Ile*/Val* Antibacterial and antifungal ND [42]
a
Desotamides B, E and F Marine Trp*-Leu-Val/Leu/Ile-Val/Leu-Asn-Gly* Antibacterial 12.5–32 μg/mL [22,124]
b
0.6–6.8 μM
b
Wollamides A and B Marine Trp*-Leu-Leu-Val/Leu-Asn-Orn* Antibacterial and 0.6–5.2 μM [124]
antituberculotic
a
Pargamicins A–D Terrestrial N-Me-3-Hy-Val*-4-Hy-Pip-N-Me-Gly-Phe- N-Hy-Ile/Val-Pip*/4-Hy-Pip*/4-one-Pip* Antibacterial 0.4–64 μg/mL [38,125]
c
Curacomycin+ Unknown 5-Cl-Trp*-Val-Leu-Ile-Orn-3-Hy-Asn* Antibacterial 9–15 mm [23]
a

56
Ulleungmycins A and B+ (Nicrophorusamide A) Terrestria 5-Cl-Trp*-Val-1Hleu/Leu-Ile-Orn-3-Hy-Asn* Antibacterial 8–32 μg/mL [50,126]
a
Thermoactinoamide A Marine Tyr*-Val-Leu-Leu-Leu-Ile* Antibacterial 35 μM [51]
a
Streptocidins A–D Terrestrial Val*-Orn-Leu-Phe-Pro-Leu-Trp/Phe-Asn-Gln-Tyr*/Trp* Antibacterial 1–10 μg/mL [127,128]
c
6–10 mm
a
Ambobactin Terrestrial Asp-Ser-Thr*-Thr-Ala-Gly-3-Hy-Pro-3-Hy-Leu-3-Me-Trp-2-ene-Trp-3-Hy-Pro* Antibacterial and antifungal 1.56–6.25 μg/mL [24]
a
Telomycin 2 Unknown Asp-Ser-Thr*-Thr-Ala-Gly-3-Hy-Pro-2-ene-Trp-3-Me-Trp-3-Hy-Leu-Pro* Antibacterial 4 μg/mL [25]
a
Ohmyungsamycins A and B Marine Val*-3-Hy-Phe-Val-N-Me-3-O-Me-Trp-N-Me-Val-Val-N-Me-Leu-Val-N-Me-Thr-Thr*-Val-N-Me-Val/ Antibacterial 1.07–4.28 μM [129]
N,N-diMe-Val
a
Ecumicin Terrestrial N, N-diMe-Val-Val-N-Me-Ile-Thr*-N-Me-Thr-Val-N-Me-Leu-Val-N-Me-Val-N-Me-4-O-Me-Trp-Val-3- Antituberculotic 0.26 μg/mL [37]
Hy-Phe-Val*

1 +
Hleu: homoleucine; : denoting that curacomycin and ulleungmycin B have the same amino acid composition but different configuration of Val, Leu and 3-Hy-Asn; *: denoting the linkage position of the ring formation.
a
MIC.
b
IC50.
c
DIZ.
Peptides 103 (2018) 48–59
P. Zhao et al.
9. Conclusions
In conclusion, compared to other bacteria, Actinobacteria represents
as a rich source of structurally complex natural peptide products that
will play an important role in the research, discovery, and development
of new antibiotics. At present, while many have been discovered, non-
specific toxicities in humans, partly known biosynthetic pathways, and
poor yield limit the benefits of these compounds. Therefore, optimiza-
tion of fermentation conditions, investigating regulatory genes in bio-
synthesis pathways, using genetic engineering technology to increase
production, and suitable structural modifications as the basis for the
synthesis of new drugs with high antibiotic activity and low toxicity
should be studied in the future.
Acknowledgments
This work was supported by grants from the National Natural
Science Foundation of China (NSFC, No. 31672530), the Basic and
Advanced Technology Research Projects of Henan Province (No.
162300410091), and the Doctoral Foundation of Henan University of
Science and Technology (No. 4022/13480021).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the
online version, at https://doi.org/10.1016/j.peptides.2018.03.011.
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