Penicillin Binding Proteins and β-Lactamases of Mycobacterium tuberculosis: Reexamination of the Historical Paradigm.
Penicillin Binding Proteins and β-Lactamases of Mycobacterium tuberculosis: Reexamination of the Historical Paradigm.
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DOI：
10.1128/msphere.00039-22
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发表时间：
2022-02-23
期刊：
影响因子：
4.8
通讯作者：
Lamichhane G
中科院分区：
文献类型：
--
作者：
Kumar G;Galanis C;Batchelder HR;Townsend CA;Lamichhane G
青霉素结合蛋白（PBPs）由于其在细菌细胞壁肽聚糖生理中的重要性以及作为最广泛使用的抗生素β-内酰胺类的靶标而被广泛研究。现有的范式认为，PBPs催化肽聚糖生物合成的最后一步，β-内酰胺抑制其活性。根据这种模式，存在一种独特的酶类，β-内酰胺酶，以使β-内酰胺失活。这种模式已经成为如何用β-内酰胺治疗细菌性疾病的基础。我们检验了这种历史观点是否准确地反映了结核分枝杆菌β-内酰胺与PBPs和β-内酰胺酶（BlaC）之间的关系。BlaC是β-内酰胺类头孢菌素亚类的主要灭活剂。然而，PBPs PonA1和PonA2比BlaC更有效地灭活青霉素和碳青霉烯类药物。这些发现表明，选择结核分枝杆菌PBPs可有效灭活几种β-内酰胺。不太为人所知的PBP， DacB, DacB1， DacB2和Rv2864c（一种推定的PBP）对所有β-内酰胺亚类的抑制都比较耐药。此外，Rv1730c对大多数β-内酰胺具有低亲和力。基于这些发现，我们得出结论，在结核分枝杆菌中，BlaC不是β-内酰胺失活的唯一来源。因此，历史范式不能准确描述β-内酰胺与结核分枝杆菌之间的关系。结核分枝杆菌是结核病的病原体，比任何其他细菌杀死的人都多。β-内酰胺类抗生素是最广泛用于治疗细菌感染的抗生素。与描述β-内酰胺与结核分枝杆菌之间关系的历史模型不同，我们发现结核分枝杆菌青霉素结合蛋白能够高效地灭活选择的β-内酰胺。
Penicillin binding proteins (PBPs) have been extensively studied due to their importance to the physiology of bacterial cell wall peptidoglycan and as targets of the most widely used class of antibiotics, the β-lactams. The existing paradigm asserts that PBPs catalyze the final step of peptidoglycan biosynthesis, and β-lactams inhibit their activities. According to this paradigm, a distinct enzyme class, β-lactamases, exists to inactivate β-lactams. This paradigm has been the basis for how bacterial diseases are treated with β-lactams. We tested whether this historical view accurately reflects the relationship between β-lactams and the PBPs and the β-lactamase, BlaC, of Mycobacterium tuberculosis. BlaC was the major inactivator of the cephalosporin subclass of β-lactams. However, the PBPs PonA1 and PonA2 inactivated penicillins and carbapenems more effectively than BlaC. These findings demonstrate that select M. tuberculosis PBPs are effective at inactivating several β-lactams. Lesser-known PBPs, DacB, DacB1, DacB2, and Rv2864c, a putative PBP, were comparably more resistant to inhibition by all β-lactam subclasses. Additionally, Rv1730c exhibited low affinity to most β-lactams. Based on these findings, we conclude that in M. tuberculosis, BlaC is not the only source of inactivation of β-lactams. Therefore, the historical paradigm does not accurately describe the relationship between β-lactams and M. tuberculosis. IMPORTANCE M. tuberculosis, the causative agent of tuberculosis, kills more humans than any other bacterium. β-lactams are the most widely used class of antibiotics to treat bacterial infections. Unlike in the historical model that describes the relationship between β-lactams and M. tuberculosis, we find that M. tuberculosis penicillin binding proteins are able to inactivate select β-lactams with high efficiency.
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影响因子：
64.8
作者：
HARTMANN, R;HOLTJE, JV;SCHWARZ, U
通讯作者：
SCHWARZ, U
影响因子：
3.2
作者：
Flores, AR;Parsons, LM;Pavelka, MS Jr
通讯作者：
Pavelka, MS Jr
影响因子：
2.8
作者：
Flores, AR;Parsons, LM;Pavelka, MS
通讯作者：
Pavelka, MS
DOI：
10.1016/j.str.2012.09.016
发表时间：
2012-12-05
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Erdemli SB;Gupta R;Bishai WR;Lamichhane G;Amzel LM;Bianchet MA
通讯作者：
Bianchet MA
影响因子：
2.9
作者：
Chow, Carmen;Xu, Hua;Blanchard, John S.
通讯作者：
Blanchard, John S.