期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 60, 期 7, 页码 4170-4175出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00371-16
关键词
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资金
- Engineering and Physical Sciences Research Council (EPSRC) [EP/M027546/1]
- Medical Research Council (MRC) [G1100135, MR/L007665/1]
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01AI100560]
- EPSRC [EP/M027546/1, EP/M022609/1] Funding Source: UKRI
- MRC [MC_PC_14103, MR/L007665/1, MC_PC_13073, G1100135, MC_PC_12020] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/M022609/1, EP/M027546/1] Funding Source: researchfish
- Medical Research Council [G1100135, MC_PC_14103, MC_PC_12020, MR/L007665/1, MC_PC_13073] Funding Source: researchfish
Acetamido derivatives of the naturally antibacterial non-beta-lactam lactivicin (LTV) have improved activity against their penicillin binding protein targets and reduced hydrolysis by beta-lactamases, but penetration into Gram-negative bacteria is still relatively poor. Here we report that modification of the LTV lactone with a catechol-type siderophore increases potency 1,000-fold against Stenotrophomonas maltophilia, a species renowned for its insusceptibility to antimicrobials. The MIC90 of modified lactone compound 17 (LTV17) against a global collection of extensively drug-resistant clinical S. maltophilia isolates was 0.063 mu g . ml(-1). Sideromimic modification does not reduce the ability of LTVs to induce production of the L1 and L2 beta-lactamases in S. maltophilia and does not reduce the rate at which LTVs are hydrolyzed by L1 or L2. We conclude, therefore, that lactivicin modification with a siderophore known to be preferentially used by S. maltophilia substantially increases penetration via siderophore uptake. LTV17 has the potential to be developed as a novel antimicrobial for treatment of infections by S. maltophilia. More generally, our work shows that sideromimic modification in a species-targeted manner might prove useful for the development of narrow-spectrum antimicrobials that have reduced collateral effects.
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