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. Nosiheptide was also highly active against Enterococcus spp and the contemporary hypervirulent BI 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 hours at 10X MIC. Furthermore, nosiheptide was found to be non-cytotoxic against mammalian cells at >> 100X MIC, and its anti-MRSA activity was not inhibited by 20% human serum. Notably, nosiheptide exhibited a significantly prolonged post-antibiotic effect (PAE) against both healthcare- and community-associated MRSA compared to 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.

YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function

“…methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae , and vancomycin-resistant enterococci. 32, 217, 218 Since the first thiopeptide micrococcin was discovered in 1948, 219 over 100 variants have been isolated. In addition to their antibiotic activity, other reported bioactivities include anticancer, antimalarial, antifungal, and immunosuppressive activities, as well as inhibition of renin and RNA polymerase (see section 3.3).…”

Structural basis and dynamics of multidrug recognition in a minimal bacterial multidrug resistance system

“…Furthermore, thiostrepton inhibits the proteasome in eukaryotic cells (42,43) exerting antimalarial (44,45) and anticancer (42)(43)(44)(45)(46)(47) activities. Despite their unique mechanism of action and their high potency against pathogens such as methicillin-resistant Staphylococcus aureus and Enterococcus faecium or penicillin-resistant Streptococcus pneumonia (48), the clinical application of thiopeptides is impeded by their considerable size and low water solubility (35,(48)(49)(50)(51). However, recent progress in thiopeptide chemical synthesis (43,52), biosynthesis (53,54), and activity screens (55) may enable the development of new thiopeptide derivatives with improved pharmaceutical properties.…”

Rapid determination of nosiheptide in feed based on dispersive SPE coupled with HPLC

“…Nosiheptide, a prototypical member of the thiopeptide antibiotic family, bears a unique indole side ring system and region‐specific hydroxyl groups within its characteristic macrocyclic core . This compound is produced by Streptomyces actuosus 40037 and can effectively inhibit the growth of gram‐positive bacteria in vitro, especially the growth of Staphylococcus aureus . Nosiheptide (Figure ) was first discovered by a French scientist in 1961 and was subsequently suggested to have a powerful effect on promoting animal growth .…”

“…Nosiheptide, a prototypical member of the thiopeptide antibiotic family, bears a unique indole side ring system and regionspecific hydroxyl groups within its characteristic macrocyclic core [1,2]. This compound is produced by Streptomyces actuosus 40037 and can effectively inhibit the growth of gram-positive bacteria in vitro, especially the growth of Staphylococcus aureus [3,4]. Nosiheptide (Figure 1) was first discovered by a French scientist in 1961 and was subsequently suggested to have a powerful effect on Article Related Abbreviations: Alumina B, basic aluminum oxide; Alumina N, neutral aluminum oxide; dSPE, dispersive solid-phase extraction; FL, fluorescence; GCB, graphitized carbon black; PLE, pressurized-liquid extraction; PSA, primary secondary amine; P-SCX, P-strong cation exchanger promoting animal growth [3].…”