期刊
ACS CHEMICAL BIOLOGY
卷 14, 期 2, 页码 296-303出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.8b01025
关键词
-
资金
- National Institutes of Health (NIH) [GM61629, AI113219]
- NIH Training Grant [T32GM075762]
- ECK Institute for Global Health at the University of Notre Dame
- Uehara Memorial Foundation
The interplay between the activities of lytic transglycosylases (LTs) and penicillin-binding proteins (PBPs) is critical for the health of the bacterial cell wall. Bulgecin A (a natural-product inhibitor of LTs) potentiates the activity of beta-lactam antibiotics (inhibitors of PBPs), underscoring this intimate mechanistic interdependence. Bulgecin A in the presence of an appropriate beta-lactam causes bulge deformation due to the formation of aberrant peptidoglycan at the division site of the bacterium. As Pseudomonas aeruginosa, a nefarious human pathogen, has 11 LT paralogs, the answer as to which LT activity correlates with beta-lactam potentiation is important and is currently unknown. Growth of P. aeruginosa PAO1 strains harboring individual transposon-insertion mutants at each of the 11 genes for LTs, in the presence of the beta-lactam antibiotic ceftazidime or meropenem, implicated the gene products of sit, mltD, and mltG (of the 11), in bulge formation and potentiation. Hence, the respective enzymes would be the targets of inhibition by bulgecin A, which was indeed documented. We further demonstrated by imaging in real time and by SEM that cell lysis occurs by the structural failure of this bulge. Upon removal of the beta-lactam antibiotic prior to lysis, P. aeruginosa experiences delayed recovery from the elongation and bulge phenotype in the presence of bulgecin A. These observations argue for a collaborative role for the target LTs in the repair of the aberrant cell wall, the absence of activities of which in the presence of bulgecin A results in potentiation of the beta-lactam antibiotic.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据