Novel Mechanisms of Beta-lactam Resistance in Staph Aureus

金黄色葡萄球菌β-内酰胺耐药的新机制

• 批准号: 10318974
• 负责人: Som Chatterjee
• 金额: $ 65.37万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318974
• 关键词: Affect; Affinity; Ampicillin; Antibiotics; Attenuated; Bacteria; Binding; Biochemical; Biological Assay; Biology; Cell Wall; Cell physiology; Cell surface; Cells; Chemicals; Clinical; Cytolysins; Data; Defect; Follow-Up Studies; Future; Gene Expression; Genetic; Genetic Transcription; Genus staphylococcus; Goals; Human; Investigation; Knowledge; Mediating; Mediator; Methicillin Resistance; Missense Mutation; Molecular Weight; Morbidity - disease rate; Mutation; Mutation Detection; Nature; Penicillin-Binding Proteins; Penicillins; Peptidyltransferase; Periodicity; Pharmaceutical Preparations; Phenotype; Physiological; Process; Production; Promoter Regions; Proteins; Proteomics; RNA; Regulation; Research; Resistance; Role; Second Messenger Systems; Signal Transduction; Staphylococcus aureus; Treatment Failure; Virulence; Virulence Factors; Yin-Yang; beta-Lactam Resistance; beta-Lactamase; beta-Lactams; cost; crosslink; experimental study; genome sequencing; in vivo; inhibitor; lead candidate; loss of function mutation; mortality; novel; novel therapeutic intervention; overexpression; pathogen; pathogenic bacteria; phosphoric diester hydrolase; promoter; resistance mechanism; resistant strain; screening; surveillance study; whole genome

Abstract We have identified a novel mode of high-level, broad-spectrum β-lactam resistance in S. aureus that is not mediated by PBP2a, the penicillin-binding protein (PBP) that confers methicillin resistance. PBP4, a non- essential PBP, and GdpP, the only known phosphodiesterase (PDE) that mediates cyclic-di-adenosine-mono- phosphate (CDA) degradation, have critical roles in this type of resistance. Mutations that enhance PBP4's ability to make a highly cross-linked bacterial cell wall and loss-of-function mutations in GdpP are the genetic basis responsible for this uncanonical resistance. The highly cross-linked cell wall formation is driven either independently or cooperatively by two distinct biochemical features of PBP4, a) structural changes in its protein due to missense mutations and b) its overexpression due to mutations in its promoter region. The loss-of-function mutations in GdpP result in elevated concentrations of CDA in bacterial cells. CDA is a newly discovered cell-signaling second messenger in bacteria which acts as an allosteric regulator by binding to its effectors (proteins and RNAs). CDA broadly affects gene expression and controls GdpP related β-lactam resistant phenotypes in a concentration dependent manner, suggesting that it is the deterministic factor in resistance. However, the precise role(s) of CDA in mediating β-lactam resistance as well as other vital processes of S. aureus is currently unknown. These functional alterations of PBP4 and GdpP likely come at the cost of bacterial virulence due to depletion of cell wall associated proteins and attenuated production of cytolysins, respectively. This indicates a unique yin-yang relationship between two key pathogenic factors of S. aureus, β-lactam resistance and virulence. We will investigate the fundamental basis of the functional changes in PBP4 and GdpP that lead to resistance and their impact on bacterial virulence. Aim 1: To determine the mechanism of PBP4-mediated β-lactam resistance and the role of PBP4 in cell wall composition. The relative contribution of PBP4 missense and promoter mutations on cell wall synthesis will be evaluated biochemically and structurally. The mechanism(s) that control pbp4 expression will be investigated to identify regulator(s) and to determine how they confer PBP4-mediated β-lactam resistance. PBP4's role on bacterial cell surface associated virulence factor expression will be determined. Aim 2: To define the role of cyclic-di-adenosine-mono-phosphate (CDA) signaling in S. aureus. Genetic and chemical proteomic approaches will be taken to identify CDA mediator/s in the bacteria that are responsible for β-lactam resistance and virulence defect. Finally, our preliminary data suggest the presence of a novel CDA specific phosphodiesterase in S. aureus besides GdpP. We will identify this novel phosphodiesterase. The proposed research will advance knowledge of basic cellular processes in S. aureus.

摘要

项目成果

Ceftaroline-Resistant, Daptomycin-Tolerant, and Heterogeneous Vancomycin-Intermediate Methicillin-Resistant Staphylococcus aureus Causing Infective Endocarditis.

头孢洛林耐药、达托霉素耐受和异种万古霉素中间甲氧西林耐药金黄色葡萄球菌引起感染性心内膜炎。

• DOI: 10.1128/aac.01235-16
• 发表时间: 2017
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Nigo,Masayuki;Diaz,Lorena;Carvajal,LinaP;Tran,TrucT;Rios,Rafael;Panesso,Diana;Garavito,JuanD;Miller,WilliamR;Wanger,Audrey;Weinstock,George;Munita,JoseM;Arias,CesarA;Chambers,HenryF
• 通讯作者: Chambers,HenryF

In Vivo Detection of Cyclic-di-AMP in Staphylococcus aureus.

• DOI: 10.1021/acsomega.2c04538
• 发表时间: 2022-09-13
• 期刊: ACS OMEGA
• 影响因子: 4.1
• 作者: Mukkayyan, Nagaraja;Poon, Raymond;Sander, Philipp N.;Lai, Li-Yin;Zubair-Nizami, Zahra;Hammond, Ming C.;Chatterjee, Som S.
• 通讯作者: Chatterjee, Som S.

PBP4-mediated β-lactam resistance among clinical strains of Staphylococcus aureus.

金黄色葡萄球菌临床菌株中 PBP4 介导的 β-内酰胺耐药性。

• DOI: 10.1093/jac/dkab201
• 发表时间: 2021
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: Satishkumar,Nidhi;Alexander,JAndrewN;Poon,Raymond;Buggeln,Emma;Argudín,MariaA;Strynadka,NatalieCJ;Chatterjee,SomS
• 通讯作者: Chatterjee,SomS

A Nonclassical Mechanism of β-Lactam Resistance in Methicillin-Resistant Staphylococcus aureus and Its Effect on Virulence.

• DOI: 10.1128/spectrum.02284-22
• 发表时间: 2022-12-21
• 期刊: Microbiology spectrum
• 影响因子: 3.7

Structural basis of broad-spectrum β-lactam resistance in Staphylococcus aureus.

• DOI: 10.1038/s41586-022-05583-3
• 发表时间: 2023-01
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Alexander, J. Andrew N.;Worrall, Liam J.;Hu, Jinhong;Vuckovic, Marija;Satishkumar, Nidhi;Poon, Raymond;Sobhanifar, Solmaz;Rosell, Federico I.;Jenkins, Joshua;Chiang, Daniel;Mosimann, Wesley A.;Chambers, Henry F.;Paetzel, Mark;Chatterjee, Som S.;Strynadka, Natalie C. J.
• 通讯作者: Strynadka, Natalie C. J.