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Surotomycin demonstrates low in vitro frequency of resistance and rapid bactericidal activity in Clostridium difficile, Enterococcus faecalis, and Enterococcus faecium.

ABSTRACT: Surotomycin (CB-183,315) is an orally administered, minimally absorbed, selective bactericidal cyclic lipopeptide in phase 3 development for the treatment of Clostridium difficile-associated diarrhea. The aim of this study was to evaluate the emergence of resistance in C. difficile (ATCC 700057 and three recent clinical isolates from the restriction endonuclease analysis groups BI, BK, and K), vancomycin-susceptible (VS) Enterococcus faecalis (ATCC 49452), vancomycin-resistant (VR) E. faecalis (ATCC 700802), VS Enterococcus faecium (ATCC 6569), and VR E. faecium (ATCC 51559) under anaerobic conditions. The rate of spontaneous resistance was below the limit of detection (<10(-8) to <10(-9)) for surotomycin at 16 and 32× the MIC for all isolates tested. Under selective pressure by serial passage, C. difficile grew in a maximum of 4 ?g/ml surotomycin (final MICs of 2 to 8 ?g/ml [4- to 16-fold higher than those of the naive control]) at day 15, with the exception of the C. difficile BK strain, which grew in 16 to 32 ?g/ml (final MICs of 8 to 32 ?g/ml [16- to 64-fold higher than those of the naive control]). Enterococci remained relatively unchanged over 15 days, growing in a maximum of 8 ?g/ml surotomycin (final MICs of 2 to 16 ?g/ml [8- to 64-fold higher than those of the naive control]). Of the isolates tested, no cross-resistance to vancomycin, rifampin, ampicillin, metronidazole, or moxifloxacin was observed. Surotomycin at 20× MIC demonstrated equally rapid bactericidal activity (? 3-log-unit reduction in CFU/ml in ? 8 h) against naive and reduced-susceptibility isolates of C. difficile, VS Enterococcus (VSE), and VR Enterococcus (VRE), except for C. difficile BK (2.6-log-unit reductions for both). These results suggest that emergence of resistance to surotomycin against C. difficile, E. faecalis, and E. faecium is likely to be rare.

SUBMITTER: Mascio CT

PROVIDER: S-EPMC4068600 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Surotomycin demonstrates low in vitro frequency of resistance and rapid bactericidal activity in Clostridium difficile, Enterococcus faecalis, and Enterococcus faecium.

Mascio Carmela T M CT Chesnel Laurent L Thorne Grace G Silverman Jared A JA

Antimicrobial agents and chemotherapy 20140505 7

Surotomycin (CB-183,315) is an orally administered, minimally absorbed, selective bactericidal cyclic lipopeptide in phase 3 development for the treatment of Clostridium difficile-associated diarrhea. The aim of this study was to evaluate the emergence of resistance in C. difficile (ATCC 700057 and three recent clinical isolates from the restriction endonuclease analysis groups BI, BK, and K), vancomycin-susceptible (VS) Enterococcus faecalis (ATCC 49452), vancomycin-resistant (VR) E. faecalis ( ...[more]

PMID: 24798273

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Project description:Enterococcus faecium has become a major opportunistic pathogen with the emergence of multidrug-resistant clones that are well-adapted to the hospital environment. As part of the vast diversity of gut microbiota, they are faced with different environmental stress, including antimicrobial pressure. By contrast, little is known about the effect of non-antibiotic molecules on bacterial physiology while numerous drugs are used in inpatients, especially those hospitalized in intensive care units (ICUs). The aim of this study was to investigate the impact of the most prescribed xenobiotics in ICUs on fitness, pathogenicity and antimicrobial resistance of E. faecium. Several phenotypic analysis was carried out and we rapidly brought to light that caspofungin, an antifungal agent belonging to the echinocandin family, seemed to have an important impact on E. faecium growth. Since the fungal target of caspofungin [beta-(1,3)-glucan synthase] is absent in enterococci, the mechanism of caspofungin action was investigated by several approaches. First, we decided to confirm this result by electronic microscopy and a peptidoglycan analysis by Ultra Performance Liquid Chromatography coupled with mass spectrometry (UPLC-MS/MS). Again, we highlighted that caspofungin even at subinhibitory concentrations (SICs) seemed to have an impact on cell wall organization especially in muropeptide precursors abundance. Then, a transcriptomic analysis was performed by RNA-seq (HiSeq 2500, Illumina) using the vanB-positive reference strain E. faecium Aus0004 in the presence or absence of caspofungin SIC (8 mg/L i.e., ¼ of the MIC). Transcriptomic analysis showed that the expression of 568 genes (19.9% of the genome) was significantly altered in the presence of caspofungin SIC, with 323 genes induced (fold change >2, p-value <0.1) and 245 genes repressed (fold change <-2, p-value <0.1). Regarding the repressed genes, the pdhABCD operon is largely downregulated (fold changes -4.3, -9.7, -6.9 and -6.4, respectively). This operon encoded components of the pyruvate deshydrogenase multienzyme complex involved in bacterial energetic pathway by the citrate cycle (i.e., TCA cycle). Moreover, it seemed that the glycerol metabolism pathway and in particular the glpOKF operon is downregulated too. The dramatic alteration of TCA seemed to have an drastic impact on bacterial cells viability indeed decrease of glycerol metabolism could explain the conformational modifications of peptidoglycan.

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Dataset Information

Surotomycin demonstrates low in vitro frequency of resistance and rapid bactericidal activity in Clostridium difficile, Enterococcus faecalis, and Enterococcus faecium.

Publications

Surotomycin demonstrates low in vitro frequency of resistance and rapid bactericidal activity in Clostridium difficile, Enterococcus faecalis, and Enterococcus faecium.

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