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Surprising alteration of antibacterial activity of 5"-modified neomycin against resistant bacteria.

ABSTRACT: A facile synthetic protocol for the production of neomycin B derivatives with various modifications at the 5'' position has been developed. The structural activity relationship (SAR) against aminoglycoside resistant bacteria equipped with various aminoglycoside-modifying enzymes (AMEs) was investigated. Enzymatic and molecular modeling studies reveal that the superb substrate promiscuity of AMEs allows the resistant bacteria to cope with diverse structural modifications despite the observation that several derivatives show enhanced antibacterial activity compared to the parent neomycin. Surprisingly, when testing synthetic neomycin derivatives against other human pathogens, two leads exhibit prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) that are known to exert a high level of resistance against clinically used aminoglycosides. These findings can be extremely useful in developing new aminoglycoside antibiotics against resistant bacteria. Our result also suggests that new biological and antimicrobial activities can be obtained by chemical modifications of old drugs.

SUBMITTER: Zhang J

PROVIDER: S-EPMC2664170 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Surprising alteration of antibacterial activity of 5"-modified neomycin against resistant bacteria.

Zhang Jianjun J Chiang Fang-I FI Wu Long L Czyryca Przemyslaw Greg PG Li Ding D Chang Cheng-Wei Tom CW

Journal of medicinal chemistry 20081201 23

A facile synthetic protocol for the production of neomycin B derivatives with various modifications at the 5'' position has been developed. The structural activity relationship (SAR) against aminoglycoside resistant bacteria equipped with various aminoglycoside-modifying enzymes (AMEs) was investigated. Enzymatic and molecular modeling studies reveal that the superb substrate promiscuity of AMEs allows the resistant bacteria to cope with diverse structural modifications despite the observation t ...[more]

PMID: 19012394

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Project description:BACKGROUND:In the context of searching for potent, safe, natural antimicrobial agents to combate the global antimicrobial resistance (AMR) phenomenon, the current study evaluates for the first time ever, the broad-spectrum antimicrobial activity of essential oil (EO) and extracts from the rare wild plant Centaurea pumilio L.. It has tremendous ethnomedicinal values; its dried root is used as a fattening agent, a treatment for bad breath and diabetes, and screened for schistosomicidal activity. METHODS:C. pumilio EO was extracted by hydrodistillation using a Clevenger apparatus. Chemical constituents of aerial part were extracted using a sequential solvent/solvent procedure employing four solvents with increasing polarities in the following order: petroleum ether, chloroform, ethyl acetate, and n-butanol. The chemical constituents were identified by GC-MS. Fifty-two microbial strains were used; twenty-six multidrug resistant (MDR), sixteen clinical, and ten reference strains. The identification of the microbial strains was performed by MALDI-TOF-MS. The antimicrobial activity of the EO and the aerial part and the root extracts was assessed through disc diffusion assay. A minimum inhibitory concentration (MIC) of the EO and extracts was determined using the broth micro-dilution method. RESULTS:The growth of reference and clinical strains was inhibited by EO, methanol, chloroform, and ethyl acetate aerial part extracts and chloroform root extract. The MDR strains growth, however, was inhibited only by EO and chloroform aerial part extract. GC-MS identified for the first time eighteen constituents from aerial part EO and chloroform extract each. EO showed antimicrobial activity against the reference, clinical, and MDR strains with MIC values of 31.25-125, 31.25-125, and 62.50-250 μg/mL, respectively. Methanol aerial part extract exhibited high antimicrobial activities with MIC values of 62.50-250 μg/mL against reference and clinical strains. Chloroform root extract displayed strong antimicrobial activity against reference and clinical strains recording MIC values of 62.50-250 μg/mL and 62.50-125 μg/mL, respectively. The chloroform aerial part extract demonstrated potent antimicrobial activity against the reference, clinical, and MDR strains with 31.25, 31.25, and 15.62 μg/mL MIC values, respectively. CONCLUSIONS:Present data unravel the C. pumilio pharmacological magnitude to discover eco-friendly potent antimicrobial agents to fight AMR phenomenon.

Dataset Information

Surprising alteration of antibacterial activity of 5"-modified neomycin against resistant bacteria.

Publications

Surprising alteration of antibacterial activity of 5"-modified neomycin against resistant bacteria.

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