Activity of the thiopeptide antibiotic nosiheptide against contemporary strains of methicillin-resistant Staphylococcus aureus

Nina M. Haste, Wdee Thienphrapa, Dan N. Tran, Sandra Loesgen, Peng Sun, Sang Jip Nam, Paul R. Jensen, William Fenical, George Sakoulas, Victor Nizet, Mary E. Hensler

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The rapid rise in antimicrobial resistance in bacteria has generated an increased demand for the development of novel therapies to treat contemporary infections, especially those caused by methicillin-resistant Staphylococcus aureus (MRSA). However, antimicrobial development has been largely abandoned by the pharmaceutical industry. We recently isolated the previously described thiopeptide antibiotic nosiheptide from a marine actinomycete strain and evaluated its activity against contemporary clinically relevant bacterial pathogens. Nosiheptide exhibited extremely potent activity against all contemporary MRSA strains tested including multiple drug-resistant clinical isolates, with MIC values ≤0.25 mg l-1. Nosiheptide was also highly active against Enterococcus spp. and the contemporary hypervirulent BI/NAP1/027 strain of Clostridium difficile but was inactive against most Gram-negative strains tested. Time-kill analysis revealed nosiheptide to be rapidly bactericidal against MRSA in a concentration-and time-dependent manner, with a nearly 2-log kill noted at 6 h at 10 × MIC. Furthermore, nosiheptide was found to be non-cytotoxic against mammalian cells at >>100 × MIC, and its anti-MRSA activity was not inhibited by 20% human serum. Notably, nosiheptide exhibited a significantly prolonged post-antibiotic effect against both healthcare-and community-associated MRSA compared with vancomycin. Nosiheptide also demonstrated in vivo activity in a murine model of MRSA infection, and therefore represents a promising antibiotic for the treatment of serious infections caused by contemporary strains of MRSA.

Original languageEnglish
Pages (from-to)593-598
Number of pages6
JournalJournal of Antibiotics
Issue number12
StatePublished - Dec 2012

Bibliographical note

Funding Information:
NMH was supported by the National Institutes of Health (NIH) Training Program in Marine Biotechnology (T32 GM067550) and a Ruth L Kirschstein National Research Service Award (NRSA) from National Institutes of Health grants (5 F31 GM090658-02). SL was supported by the German Research Foundation (DFG). WF, VN, PRJ and MEH were supported by National Institutes of Health grant GM084350. PRJ and WF acknowledge financial support from the NIH Fogerty Center International Cooperative Biodiversity Groups program (grant U01-TW00007-401). We thank K Freel and C Kauffman for assistance with fieldwork and W Aalbersberg (University of the South Pacific) for providing laboratory space and facilitating the field collections. We gratefully acknowledge the people of Fiji for their hospitality and permission to collect samples from their local waters. We are also grateful to Diane M Citron and Ellie Goldstein MD of RM Alden Research Laboratories (Culver City, CA, USA) for performing susceptibility testing against Clostridium difficile.


  • contemporary MRSA
  • marine actinomycete
  • nosiheptide
  • thiopeptide


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