Servicio de Microbiología and Unidad de Investigación, Hospital Son Espases-Instituto de Investigación Sanitaria de Baleares (IdISBa), 07120 Palma, Illes Balears, Spain.
FEMS Microbiol Rev. 2017 Nov 1;41(6):781-815. doi: 10.1093/femsre/fux043.
This review deeply addresses for the first time the diversity, regulation and mechanisms leading to mutational overexpression of intrinsic β-lactamases from non-fermenting and other non-Enterobacteriaceae Gram-negative opportunistic pathogens. After a general overview of the intrinsic β-lactamases described so far in these microorganisms, including circa. 60 species and 100 different enzymes, we review the wide array of regulatory pathways of these β-lactamases. They include diverse LysR-type regulators, which control the expression of β-lactamases from relevant nosocomial pathogens such as Pseudomonas aeruginosa or Stenothrophomonas maltophilia or two-component regulators, with special relevance in Aeromonas spp., along with other pathways. Likewise, the multiple mutational mechanisms leading to β-lactamase overexpression and β-lactam resistance development, including AmpD (N-acetyl-muramyl-L-alanine amidase), DacB (PBP4), MrcA (PPBP1A) and other PBPs, BlrAB (two-component regulator) or several lytic transglycosylases among others, are also described. Moreover, we address the growing evidence of a major interplay between β-lactamase regulation, peptidoglycan metabolism and virulence. Finally, we analyse recent works showing that blocking of peptidoglycan recycling (such as inhibition of NagZ or AmpG) might be useful to prevent and revert β-lactam resistance. Altogether, the provided information and the identified gaps should be valuable for guiding future strategies for combating multidrug-resistant Gram-negative pathogens.
这篇综述首次深入探讨了非发酵和其他非肠杆菌科革兰氏阴性机会致病菌固有β-内酰胺酶的多样性、调控机制和导致突变过表达的机制。在概述了迄今为止在这些微生物中描述的大约 60 种和 100 种不同的酶的固有β-内酰胺酶之后，我们回顾了这些β-内酰胺酶的广泛调控途径。它们包括各种 LysR 型调节剂，这些调节剂控制着铜绿假单胞菌或嗜麦芽寡养单胞菌等相关医院病原体中β-内酰胺酶的表达，或者是双组分调节剂，在气单胞菌属中具有特殊的相关性，以及其他途径。同样，导致β-内酰胺酶过表达和β-内酰胺耐药发展的多种突变机制，包括 AmpD（N-乙酰基-胞壁酰-L-丙氨酸酰胺酶）、DacB（PBP4）、MrcA（PPBP1A）和其他 PBPs、BlrAB（双组分调节剂）或几种溶菌转糖苷酶等，也都有描述。此外，我们还探讨了β-内酰胺酶调控、肽聚糖代谢和毒力之间主要相互作用的日益增多的证据。最后，我们分析了最近的研究工作，表明阻断肽聚糖循环（如抑制 NagZ 或 AmpG）可能有助于预防和逆转β-内酰胺耐药性。总的来说，提供的信息和确定的差距应该对指导未来对抗多药耐药革兰氏阴性病原体的策略具有重要价值。
