Biomedicine Discovery Institute, Infection and Immunity Program and Department of Microbiology, Monash University, Clayton, Australia.
Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, Australia.
Adv Exp Med Biol. 2019;1145:55-71. doi: 10.1007/978-3-030-16373-0_5.
Polymyxin antibiotics are increasingly being used as last-line therapeutic options against a number of multidrug resistant bacteria. These antibiotics show strong bactericidal activity against a range of Gram-negative bacteria, but with the increased use of these antibiotics resistant strains are emerging at an alarming rate. Furthermore, some Gram-negative species, such as Neisseria meningitidis, Proteus mirabilis and Burkholderia spp., are intrinsically resistant to the action of polymyxins. Most identified polymyxin resistance mechanisms in Gram-negative bacteria involve changes to the lipopolysaccharide (LPS) structure, as polymyxins initially interact with the negatively charged lipid A component of LPS. The controlled addition of positively charged residues such as 4-amino--arabinose, phosphoethanolamine and/or galactosamine to LPS results in a reduced negative charge on the bacterial surface and therefore reduced interaction between the polymyxin and the LPS. Polymyxin resistant species produce LPS that intrinsically contains one or more of these additions. While the genes necessary for most of these additions are chromosomally encoded, plasmid-borne phosphoethanolamine transferases (mcr-1 to mcr-8) have recently been identified and these plasmids threaten to increase the rate of dissemination of clinically relevant colistin resistance. Uniquely, Acinetobacter baumannii can also become highly resistant to polymyxins via spontaneous mutations in the lipid A biosynthesis genes lpxA, lpxC or lpxD such that they produce no LPS or lipid A. A range of other non-LPS-dependent polymyxin resistance mechanisms has also been identified in bacteria, but these generally result in only low levels of resistance. These include increased anionic capsular polysaccharide production in Klebsiella pneumoniae, expression of efflux systems such as MtrCDE in N. meningitidis, and altered expression of outer membrane proteins in a small number of species.
多黏菌素类抗生素作为治疗多种耐药菌的最后一线治疗选择，应用日益广泛。这些抗生素对多种革兰氏阴性菌具有很强的杀菌活性，但随着这些抗生素的广泛使用，耐药菌株的出现速度令人震惊。此外，一些革兰氏阴性菌，如脑膜炎奈瑟菌、奇异变形杆菌和伯克霍尔德菌等，对多黏菌素的作用具有固有抗性。革兰氏阴性菌中大多数已确定的多黏菌素耐药机制涉及到脂多糖（LPS）结构的改变，因为多黏菌素最初与 LPS 的负电荷脂质 A 成分相互作用。LPS 中添加带正电荷的残基，如 4-氨基-D-阿拉伯糖、磷酸乙醇胺和/或半乳糖胺，会导致细菌表面负电荷减少，从而减少多黏菌素与 LPS 之间的相互作用。多黏菌素耐药菌产生的 LPS 内在地含有这些添加物中的一种或多种。虽然大多数这些添加物所需的基因都在染色体上编码，但最近发现了质粒携带的磷酸乙醇胺转移酶（mcr-1 到 mcr-8），这些质粒有可能增加临床相关黏菌素耐药性的传播速度。独特的是，鲍曼不动杆菌也可以通过脂质 A 生物合成基因 lpxA、lpxC 或 lpxD 的自发突变而对多黏菌素产生高度耐药性，从而导致它们不产生 LPS 或脂质 A。在细菌中还发现了一系列其他非 LPS 依赖性多黏菌素耐药机制，但这些机制通常只导致低度耐药。其中包括肺炎克雷伯菌中阴离子荚膜多糖产生增加、脑膜炎奈瑟菌中 MtrCDE 等外排系统的表达，以及少数物种中膜蛋白表达的改变。
