The clinical and epidemiological threat of the growing antimicrobial resistance in Gram-negative pathogens, particularly for β-lactams, the most frequently used and relevant antibiotics, urges research to find new therapeutic weapons to combat the infections caused by these microorganisms. An essential previous step in the development of these therapeutic solutions is to identify their potential targets in the biology of the pathogen. This is precisely what we sought to do in this review specifically regarding the barely exploited field analyzing the interplay among the biology of the peptidoglycan and related processes, such as β-lactamase regulation and virulence. Hence, here we gather, analyze, and integrate the knowledge derived from published works that provide information on the topic, starting with those dealing with the historically neglected essential role of the Gram-negative peptidoglycan in virulence, including structural, biogenesis, remodeling, and recycling aspects, in addition to proinflammatory and other interactions with the host. We also review the complex link between intrinsic β-lactamase production and peptidoglycan metabolism, as well as the biological costs potentially associated with the expression of horizontally acquired β-lactamases. Finally, we analyze the existing evidence from multiple perspectives to provide useful clues for identifying targets enabling the future development of therapeutic options attacking the peptidoglycan-virulence interconnection as a key weak point of the Gram-negative pathogens to be used, if not to kill the bacteria, to mitigate their capacity to produce severe infections.

中文翻译：

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肽聚糖生物学与革兰氏阴性病原体毒力之间的相互作用。


革兰氏阴性病原体（特别是最常用和相关的抗生素β-内酰胺）日益增长的抗菌药物耐药性所带来的临床和流行病学威胁，促使研究人员寻找新的治疗武器来对抗这些微生物引起的感染。开发这些治疗解决方案的一个重要的前期步骤是确定它们在病原体生物学中的潜在靶点。这正是我们在这篇综述中想要做的，特别是在分析肽聚糖生物学和相关过程（例如 β-内酰胺酶调节和毒力）之间相互作用的几乎没有开发的领域。因此，在这里，我们收集、分析和整合从已发表的提供有关该主题信息的著作中获得的知识，从那些涉及历史上被忽视的革兰氏阴性肽聚糖在毒力中的重要作用的知识开始，包括结构、生物发生、重塑和除了促炎和与宿主的其他相互作用之外，回收方面也有作用。我们还回顾了内在β-内酰胺酶产生和肽聚糖代谢之间的复杂联系，以及与水平获得的β-内酰胺酶表达潜在相关的生物成本。最后，我们从多个角度分析现有证据，为识别目标提供有用的线索，从而使未来能够开发治疗方案，攻击肽聚糖-毒力互连作为革兰氏阴性病原体的关键弱点，即使不是杀死革兰氏阴性病原体。细菌，以减轻其产生严重感染的能力。