Poole K
Department of Microbiology and Immunology, Queen's University, Kingston, Ontario, Canada.
J Appl Microbiol. 2002;92 Suppl:55S-64S.
Resistance to antibiotics is increasingly commonplace amongst important human pathogens. Although the mechanism(s) of resistance vary from agent to agent they typically involve one or more of: alteration of the drug target in the bacterial cell, enzymatic modification or destruction of the drug itself, or limitation of drug accumulation as a result of drug exclusion or active drug efflux. While most of these are agent specific, providing resistance to a single antimicrobial or class of antimicrobial, there are currently numerous examples of efflux systems that accommodate and, thus, provide resistance to a broad range of structurally unrelated antimicrobials -- so-called multidrug efflux systems. Resistance to biocides is less common and likely reflects the multiplicity of targets within the cell as well as the general lack of known detoxifying enzymes. Resistance typically results from cellular changes that impact on biocide accumulation, including cell envelope changes that limit uptake, or expression of efflux mechanisms. Still, target site mutations leading to biocide resistance, though rare, are known. Intriguingly, many multidrug efflux systems also accommodate biocides (e.g. triclosan) such that strains expressing these are both antibiotic- and biocide-resistant. Indeed, concern has been expressed regarding the potential for agents such as triclosan to select for strains resistant to multiple clinically-relevant antibiotics. Some of the better characterized examples of such multidrug efflux systems can be found in the opportunistic pathogen Pseudomonas aeruginosa where they play an important role in the noted intrinsic and acquired resistance of this organism to antibiotics and triclosan. These tripartite pumps include an integral inner membrane drug-proton antiporter, an outer membrane- and periplasm-spanning channel-forming protein and a periplasmic link protein that joins these two. Expression of efflux genes is governed minimally by the product of a linked regulatory gene that is in most cases the target for mutation in multidrug resistant strains hyperexpressing these efflux systems. Issues for consideration include the natural function of these efflux systems and the therapeutic potential of targeting these systems in combating acquired multidrug resistance.
抗生素耐药性在重要的人类病原体中日益普遍。尽管耐药机制因病原体而异，但通常涉及以下一种或多种情况：细菌细胞中药物靶点的改变、药物本身的酶促修饰或破坏，或由于药物排斥或主动药物外排导致药物积累受限。虽然其中大多数是病原体特异性的，仅对单一抗菌药物或一类抗菌药物产生耐药性，但目前有许多外排系统的例子，这些系统能够容纳并因此对多种结构不相关的抗菌药物产生耐药性——即所谓的多药外排系统。对杀菌剂的耐药性不太常见，这可能反映了细胞内靶点的多样性以及已知解毒酶的普遍缺乏。耐药性通常是由影响杀菌剂积累的细胞变化引起的，包括限制摄取的细胞包膜变化或外排机制的表达。不过，导致杀菌剂耐药性的靶点突变虽然罕见，但也是已知的。有趣的是，许多多药外排系统也能容纳杀菌剂（如三氯生），因此表达这些系统的菌株对抗生素和杀菌剂都具有耐药性。事实上，人们已经对三氯生等药物选择对多种临床相关抗生素耐药的菌株的可能性表示担忧。在机会性病原体铜绿假单胞菌中可以找到一些特征较为明确的此类多药外排系统的例子，它们在该生物体对抗生素和三氯生的固有和获得性耐药性中发挥着重要作用。这些三联泵包括一个整合的内膜药物 - 质子反向转运体、一个跨外膜和周质的通道形成蛋白以及一个连接这两者的周质连接蛋白。外排基因的表达至少受一个相关调控基因产物的控制，在大多数情况下，该调控基因是高表达这些外排系统的多药耐药菌株中发生突变的靶点。需要考虑的问题包括这些外排系统的天然功能以及针对这些系统对抗获得性多药耐药性的治疗潜力。
