A New Antibiotic, Multhiomycin

Takano, Teruo; Endō, Toyoshige; Shimazu, Akira; Yoshida, Rieko; Suzuki, Yoko; Ōtake, Noboru; Yonehara, Hiroshi

doi:10.7164/antibiotics.23.231

Cited by 26 publications

(18 citation statements)

References 8 publications

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“…Nosiheptide (also known as multhiomycin 309–311 ), was first isolated in 1970 312 and is the most studied member of this group (Figure 19). The discovery of the nosiheptide BGC ( nos ) has provided many insights.…”

Section: Thiopeptidesmentioning

confidence: 99%

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

et al. 2017

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With advances in sequencing technology, uncharacterized proteins and domains of unknown function (DUFs) are rapidly accumulating in sequence databases and offer an opportunity to discover new protein chemistry and reaction mechanisms. The focus of this review, the formerly enigmatic YcaO superfamily (DUF181), has been found to catalyze a unique phosphorylation of a ribosomal peptide backbone amide upon attack by different nucleophiles. Established nucleophiles are the side chains of Cys, Ser, and Thr which gives rise to azoline/azole biosynthesis in ribosomally synthesized and posttranslationally modified peptide (RiPP) natural products. However, much remains unknown about the potential for YcaO proteins to collaborate with other nucleophiles. Recent work suggests potential in forming thioamides, macroamidines, and possibly additional post-translational modifications. This review covers all knowledge through mid-2016 regarding the biosynthetic gene clusters (BGCs), natural products, functions, mechanisms, and applications of YcaO proteins and outlines likely future research directions for this protein superfamily.

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Section: Thiopeptidesmentioning

confidence: 99%

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

et al. 2017

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“…Nosiheptide, known as multhiomycin, was originally isolated in 1970 [192] and identified from an anti-MRSA screen of marine-derived actinomycete extract libraries by Haste et al in 2012 [193]. Structurally, this compound is similar to the oral cyclic thiopeptide LFF571, a phase 2 clinical candidate for the treatment of moderate CDI [139].…”

Section: Newer Agents For CDImentioning

confidence: 99%

Progress in the Discovery of Treatments for C. difficile Infection: A Clinical and Medicinal Chemistry Review

Tsutsumi¹,

Owusu²,

Hurdle³

et al. 2013

CTMC

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Clostridium difficile is an anaerobic, Gram-positive pathogen that causes C. difficile infection, which results in significant morbidity and mortality. The incidence of C. difficile infection in developed countries has become increasingly high due to the emergence of newer epidemic strains, a growing elderly population, extensive use of broad spectrum antibiotics, and limited therapies for this diarrheal disease. Because treatment options currently available for C. difficile infection have some drawbacks, including cost, promotion of resistance, and selectivity problems, new agents are urgently needed to address these challenges. This review article focuses on two parts: the first part summarizes current clinical treatment strategies and agents under clinical development for C. difficile infection; the second part reviews newly reported anti-difficile agents that have been evaluated or reevaluated in the last five years and are in the early stages of drug discovery and development. Antibiotics are divided into natural product inspired and synthetic small molecule compounds that may have the potential to be more efficacious than currently approved treatments. This includes potency, selectivity, reduced cytotoxicity, and novel modes of action to prevent resistance.

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“…2,3 Nosiheptide, also referred to historically as multhiomycin, was originally isolated in 1970 and shown to be structurally similar to thiostrepton. 4,5 Several thiopeptide antibiotics including nosiheptide block protein synthesis by the inhibition of elongation factors Tu and G. 6 Historically, nosiheptide has been used as a growth-promoting additive in animal feed 7 but was never developed further as a human therapeutic.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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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. 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.

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A New Antibiotic, Multhiomycin

Cited by 26 publications

References 8 publications

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

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

Progress in the Discovery of Treatments for C. difficile Infection: A Clinical and Medicinal Chemistry Review

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

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