title: Activity of the thiopeptide antibiotic nosiheptide against contemporary strains of methicillin-resistant Staphylococcus aureus.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA 92093-0687, USA.
authors.forename: Nina M
authors.initials: NM
authors.lastname: Haste
authors.forename: Wdee
authors.initials: W
authors.lastname: Thienphrapa
authors.forename: Dan N
authors.initials: DN
authors.lastname: Tran
authors.forename: Sandra
authors.initials: S
authors.lastname: Loesgen
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.forename: Sang-Jip
authors.initials: SJ
authors.lastname: Nam
authors.forename: Paul R
authors.initials: PR
authors.lastname: Jensen
authors.forename: William
authors.initials: W
authors.lastname: Fenical
authors.forename: George
authors.initials: G
authors.lastname: Sakoulas
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Mary E
authors.initials: ME
authors.lastname: Hensler
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006367:HeLa Cells; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013302:Streptomyces / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D013844:Thiazoles; D014640:Vancomycin; C014134:nosiheptide