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Initial efforts toward the optimization of arylomycins for antibiotic activity.

ABSTRACT: While most clinically used antibiotics were derived from natural products, the isolation of new broad-spectrum natural products has become increasingly rare and narrow-spectrum agents are typically deemed unsuitable for development because of intrinsic limitations of their scaffold or target. However, it is possible that the spectrum of a natural product antibiotic might be limited by specific resistance mechanisms in some bacteria, such as target mutations, and the spectra of such "latent" antibiotics might be reoptimized by derivatization, just as has been done with clinically deployed antibiotics. We recently showed that the spectrum of the arylomycin natural product antibiotics, which act via the novel mechanism of inhibiting type I signal peptidase, is broader than previously believed and that resistance in several key human pathogens is due to the presence of a specific Pro residue in the target peptidase that disrupts interactions with the lipopeptide tail of the antibiotic. To begin to test whether this natural resistance might be overcome by derivatization, we synthesized analogues with altered lipopeptide tails and identified several with an increased spectrum of activity against S. aureus. The data support the hypothesis that the arylomycins are latent antibiotics, suggest that their spectrum may be optimized by derivatization, and identify a promising scaffold upon which future optimization efforts might focus.

SUBMITTER: Roberts TC

PROVIDER: S-EPMC3151006 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Initial efforts toward the optimization of arylomycins for antibiotic activity.

Roberts Tucker C TC Schallenberger Mark A MA Liu Jian J Smith Peter A PA Romesberg Floyd E FE

Journal of medicinal chemistry 20110628 14

While most clinically used antibiotics were derived from natural products, the isolation of new broad-spectrum natural products has become increasingly rare and narrow-spectrum agents are typically deemed unsuitable for development because of intrinsic limitations of their scaffold or target. However, it is possible that the spectrum of a natural product antibiotic might be limited by specific resistance mechanisms in some bacteria, such as target mutations, and the spectra of such "latent" anti ...[more]

PMID: 21630667

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Project description:IntroductionUrinary tract infections (UTI) are commonly encountered in the emergency department (ED). ED culture follow up is an important tool to provide the appropriate therapy after the identification of the causative pathogen. There is a growing body of evidence for the positive role of pharmacists in following up the ED cultures. The purpose of this study was to compare pharmacist driven urine culture follow ups to the nurse-practitioner (NP) driven follow ups in term of the appropriateness of antibiotic selections in patients with resistant isolates, inappropriately treated asymptomatic bacteriuria, and inappropriately chosen antibiotic.MethodologyThis was a retrospective pre-post intervention study divided into a two group period to compare pharmacist to NP led ED culture follow up interventions. Statistical Package for Social Sciences (SPSS) version 20 was used for analysis. Student's t-test was used for continuous variables and Chi-square test/or fisher's-exact test when appropriate were used for the primary outcome.ResultsFifty-five patients (25.7%) and 102 (34%) met the inclusion criteria in the pharmacist arm and in the NP arm, respectively. Escherichia coli was the most commonly isolated pathogen in both arms. Asymptomatic bacteriuria was often treated in the ED in both groups (45/157, 28.7%) and there were no efforts in discontinuation of antibiotics in these patients. Neither the interventions group nor the no interventions groups were statistically different between the pharmacist and NP arms (P 0.0778), (P 0.797), respectively.ConclusionNo statistically significant difference was observed between pharmacist driven monitoring and NP driven monitoring. In our institution, asymptomatic bacteriuria was commonly treated even in the absence of indications. We recommend that Pharmacists' roles in the ED cultures follow up be expanded to include antibiotic discontinuation in patients who meet asymptomatic bacteriuria criteria or have confirmed negative urine culture.

Dataset Information

Initial efforts toward the optimization of arylomycins for antibiotic activity.

Publications

Initial efforts toward the optimization of arylomycins for antibiotic activity.

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