In vitro and in vivo activities of antibiotic PM181104.
Drug resistance has become a global threat that, if not addressed, may return us to the preantibiotic era. A way to overcome the problem of growing incidence of global antibiotic resistance is to introduce compounds belonging to classes that are new to the clinic. During a screening of the marine microbial extract library for new antibiotics, one of the extracts showed promising antibacterial activity against Gram-positive organisms. Bioactivity-guided isolation and characterization of active metabolites led to the discovery of a novel thiazolyl cyclic-peptide antibiotic, PM181104. It was isolated and characterized from a marine sponge-associated actinobacterium strain of the genus Kocuria (MTCC 5269). The compound exhibited a potent in vitro antibacterial activity against a broad range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). The MIC values evaluated for the compound were found to be in the single-digit nanomolar range. In in vivo studies of PM181104 in a BALB/c murine septicemia model, the compound displayed 100% effective dose (ED100) values of 2.5 and 5.0 mg/kg of body weight against MRSA and 10.0 mg/kg against VRE. In this report, in vitro and in vivo studies of PM181104 are described.
Piramal Enterprises Limited, Goregaon, Mumbai, India.
Girish
G
Mahajan
Becky
B
Thomas
Rajashri
R
Parab
Zarine E
ZE
Patel
Sandip
S
Kuldharan
Vijayaphanikumar
V
Yemparala
Prabhu Dutt
PD
Mishra
Prafull
P
Ranadive
Lisette
L
D'Souza
Koteppa
K
Pari
H
H
Sivaramkrishnan
D039903:Actinobacteria / Q000737:chemistry*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology*; D059001:Aquatic Organisms / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D016983:Enterococcus / Q000187:drug effects / Q000254:growth & development; D005260:Female; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D010456:Peptides, Cyclic / Q000302:isolation & purification / Q000494:pharmacology*; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology; D020713:Vancomycin Resistance / Q000187:drug effects
D000900:Anti-Bacterial Agents; D010456:Peptides, Cyclic; C583478:kocurin