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.