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Molecular mechanism of cephalosporin resistance of N. gonorrhoeae conferred by mutated PBP2

PBP2突变导致淋病奈瑟菌头孢菌素耐药的分子机制

基本信息

批准号：
10467153
负责人：
Christopher Davies
金额：
$ 72.83万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-10 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10467153
关键词：
Active Sites Acylation Alleles Antibiotic Resistance Antibiotics Arthritis Behavior Binding Biological Process Cefixime Ceftriaxone Cell Wall Cephalosporin Resistance Cephalosporins Complex Contracts Crystallization Deuterium Development Female Goals Gonorrhea Growth HIV Hydrogen Impairment Individual Infection Infertility Investigation Lead Molecular Molecular Conformation Monobactams Morphology Mosaicism Movement Mutate Mutation Neisseria gonorrhoeae Organism Pelvic Inflammatory Disease Penicillin Binding Protein 2 Peptides Peptidoglycan Peptidyltransferase Process Protein Dynamics Proteins Public Health Reaction Relaxation Resistance Resolution Risk Role Serine Sexually Transmitted Agents Sexually Transmitted Diseases Side Structure Translating Variant X-Ray Crystallography antimicrobial beta-Lactams design experimental study fitness loss of function molecular dynamics mutant preservation resistance mechanism resistance mutation resistant strain sex

项目摘要

Project Summary Neisseria gonorrhoeae, the causative agent for the sexually transmitted infection gonorrhea, is responsible for over 800,000 infections annually in the U.S. and 78 million cases worldwide. Untreated or untreatable infections can lead to infertility, pelvic inflammatory disease (PID) in females, gonococcal arthritis in both sexes, and an increased risk of both contracting and transmitting HIV. Over the past several decades, the inexorable increase of resistance in this organism toward multiple classes of antibiotics has severely limited treatment options for gonococcal infections. Most alarmingly, resistance against the extended-spectrum cephalosporin (ESC) ceftriaxone poses a serious threat to public health. This situation requires an understanding of antibiotic resistance at the molecular level in order to enable design of new antimicrobials. ESC resistance of N. gonorrhoeae is conferred by mutated forms of penicillin-binding protein 2 (PBP2). In this application, we propose to elucidate the molecular mechanism of resistance, with the overarching hypothesis that mutations in PBP2 restrict the molecular dynamics of the protein. It builds upon our recent understanding of the interactions made by wild-type PBP2 when bound by ESCs and how conformational changes associated with binding and acylation appear restricted in PBP2 derived from ESCR strains. The investigation comprises three aims: Specific Aim 1 is a structure-function analysis of wild-type PBP2 to investigate the importance of specific interactions formed when PBP2 is bound and acylated by cephalosporins. In Specific Aim 2, we will elucidate how key mutations present in PBP2 from ESCR strains of N. gonorrhoeae reduce inactivation by cephalosporins while retaining sufficient biological function to support growth of the organism. Finally, Specific Aim 3 will examine the behavior of PBP2 variants in solution to determine whether mutations hinder protein dynamics. By revealing the molecular mechanisms of how mutations in PBP2 overcome the lethal action of β-lactams, these investigations will enable new strategies for the development of replacement anti-gonococcal agents.

项目总结