期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 63, 期 5, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00105-19
关键词
ESBL; beta-lactam; beta-lactamase inhibitor; penicillanic acid sulfone
资金
- Allecra
- Cleveland Department of Veterans Affairs, the Veterans Affairs Merit Review Program from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service [BX002872, BX001974]
- Geriatric Research Education and Clinical Center [VISN 10]
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01AI100560, R01AI063517, R01AI072219]
Impeding, as well as reducing, the burden of antimicrobial resistance in Gram-negative pathogens is an urgent public health endeavor. Our current antibiotic armamentarium is dwindling, while major resistance determinants (e.g., extended-spectrum beta-lactamases [ESBLs]) continue to evolve and disseminate around the world. One approach to attack this problem is to develop novel therapies that will protect our current agents. AAI101 is a novel penicillanic acid sulfone beta-lactamase inhibitor similar in structure to tazobactam, with one important difference. AAI101 possesses a strategically placed methyl group that gives the inhibitor a net neutral charge, enhancing bacterial cell penetration. AAI101 paired with cefepime, also a zwitterion, is in phase III of clinical development for the treatment of serious Gram-negative infections. Here, AAI101 was found to restore the activity of cefepime against class A ESBLs (e.g., CTX-M-15) and demonstrated increased potency compared to that of piperacillin-tazobactam when tested against an established isogenic panel. The enzymological properties of AAI101 further revealed that AAI101 possessed a unique mechanism of beta-lactamase inhibition compared to that of tazobactam. Additionally, upon reaction with AAI101, CTX-M-15 was modified to an inactive state. Notably, the in vivo efficacy of cefepime-AAI101 was demonstrated using a mouse septicemia model, indicating the ability of AAI101 to bolster significantly the therapeutic efficacy of cefepime in vivo. The combination of AAI101 with cefepime represents a potential carbapenem-sparing treatment regimen for infections suspected to be caused by Enterobacteriaceae expressing ESBLs.
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