Slt, MltD, and MltG of Pseudomonas aeruginosa as Targets of Bulgecin A in Potentiation of β-Lactam Antibiotics.
Slt, MltD, and MltG of Pseudomonas aeruginosa as Targets of Bulgecin A in Potentiation of β-Lactam Antibiotics.
复制标题
DOI：
10.1021/acschembio.8b01025
复制
发表时间：
2019-02-15
影响因子：
4
通讯作者：
Mobashery S
中科院分区：
文献类型：
--
作者：
Dik DA;Madukoma CS;Tomoshige S;Kim C;Lastochkin E;Boggess WC;Fisher JF;Shrout JD;Mobashery S
酵解转糖基化酶（LTs）与青霉素结合蛋白（PBPs）之间的相互作用对细菌细胞壁的健康至关重要。Bulgecin A （LTs的天然产物抑制剂）增强了β-内酰胺类抗生素（PBPs抑制剂）的活性，强调了这种密切的机制相互依赖。Bulgecin A在适当的β-内酰胺存在下，由于在细菌分裂部位形成异常肽聚糖而引起凸起变形。由于铜绿假单胞菌是一种邪恶的人类病原体，有11种LT类似物，因此LT活性与β-内酰胺增强相关的答案很重要，目前尚不清楚。在β-内酰胺类抗生素头孢他啶或美罗培南存在的情况下，铜绿假单胞菌PAO1菌株在11个LTs基因中的每一个基因上都含有单个转座子插入突变体，其生长与slt、mltD和mltG（11个中的）基因产物在隆起形成和增强中的作用有关。因此，相应的酶将是bulgecin A抑制的目标，这确实是有文献记载的。我们通过实时成像和扫描电镜进一步证明，细胞裂解是由这个凸起的结构破坏引起的。在裂解前去除β-内酰胺抗生素后，P. aeruginosa在bulgecin a的存在下经历了从伸长和凸起表型的延迟恢复。这些观察结果表明目标lt在修复异常细胞壁中的协同作用，在bulgecin a的存在下缺乏其活性导致β-内酰胺抗生素的增强。
The interplay between the activities of lytic transglycosylases (LTs) and penicillin-binding proteins (PBPs) is critical for the health of bacterial cell wall. Bulgecin A (a natural-product inhibitor of LTs) potentiates the activity of β-lactam antibiotics (inhibitors of PBPs), underscoring this intimate mechanistic interdependence. Bulgecin A in the presence of an appropriate β-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 β-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 β-lactam antibiotic ceftazidime or meropenem, implicated the gene products of slt, mltD, and mltG (of the eleven), 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 β-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 β-lactam antibiotic.
登录
查看更多内容
影响因子：
14.9
作者：
Balasubramanian D;Schneper L;Kumari H;Mathee K
通讯作者：
Mathee K
影响因子：
4.6
作者：
Byun B;Mahasenan KV;Dik DA;Marous DR;Speri E;Kumarasiri M;Fisher JF;Hermoso JA;Mobashery S
通讯作者：
Mobashery S
外膜生物发生。
影响因子：
10.5
作者：
Konovalova A;Kahne DE;Silhavy TJ
通讯作者：
Silhavy TJ
影响因子：
5.3
作者：
Burrows, Lori L.
通讯作者：
Burrows, Lori L.
影响因子：
3.2
作者：
Kraft, AR;Prabhu, J;Höltje, JV
通讯作者：
Höltje, JV