Morita Yuji, Tomida Junko, Kawamura Yoshiaki
Department of Microbiology, School of Pharmacy, Aichi Gakuin University, Nagoya Japan.
Front Microbiol. 2014 Jan 8;4:422. doi: 10.3389/fmicb.2013.00422.
Infections caused by Pseudomonas aeruginosa often are hard to treat; inappropriate chemotherapy readily selects multidrug-resistant P. aeruginosa. This organism can be exposed to a wide range of concentrations of antimicrobials during treatment; learning more about the responses of P. aeruginosa to antimicrobials is therefore important. We review here responses of the bacterium P. aeruginosa upon exposure to antimicrobials at levels below the inhibitory concentration. Carbapenems (e.g., imipenem) have been shown to induce the formation of thicker and more robust biofilms, while fluoroquinolones (e.g., ciprofloxacin) and aminoglycosides (e.g., tobramycin) have been shown to induce biofilm formation. Ciprofloxacin also has been demonstrated to enhance the frequency of mutation to carbapenem resistance. Conversely, although macrolides (e.g., azithromycin) typically are not effective against P. aeruginosa because of the pseudomonal outer-membrane impermeability and efflux, macrolides do lead to a reduction in virulence factor production. Similarly, tetracycline is not very effective against this organism, but is known to induce the type-III secretion system and consequently enhance cytotoxicity of P. aeruginosa in vivo. Of special note are the effects of antibacterials and disinfectants on pseudomonal efflux systems. Sub-inhibitory concentrations of protein synthesis inhibitors (aminoglycosides, tetracycline, chloramphenicol, etc.) induce the MexXY multidrug efflux system. This response is known to be mediated by interference with the translation of the leader peptide PA5471.1, with consequent effects on expression of the PA5471 gene product. Additionally, induction of the MexCD-OprJ multidrug efflux system is observed upon exposure to sub-inhibitory concentrations of disinfectants such as chlorhexidine and benzalkonium. This response is known to be dependent upon the AlgU stress response factor. Altogether, these biological responses of P. aeruginosa provide useful clues for the improvement and optimization of chemotherapy in order to appropriately treat pseudomonal infections while minimizing the emergence of resistance.
铜绿假单胞菌引起的感染通常难以治疗；不恰当的化疗很容易筛选出多重耐药的铜绿假单胞菌。在治疗过程中，这种细菌可能会接触到各种浓度的抗菌药物；因此，更多地了解铜绿假单胞菌对抗菌药物的反应很重要。我们在此回顾铜绿假单胞菌在接触低于抑制浓度的抗菌药物时的反应。碳青霉烯类药物（如亚胺培南）已被证明可诱导形成更厚、更坚固的生物膜，而氟喹诺酮类药物（如环丙沙星）和氨基糖苷类药物（如妥布霉素）已被证明可诱导生物膜形成。环丙沙星还被证明可提高对碳青霉烯类耐药的突变频率。相反，尽管大环内酯类药物（如阿奇霉素）由于假单胞菌外膜的不透性和外排作用通常对铜绿假单胞菌无效，但大环内酯类药物确实会导致毒力因子产生减少。同样，四环素对这种细菌不是很有效，但已知会诱导III型分泌系统，从而增强铜绿假单胞菌在体内的细胞毒性。特别值得注意的是抗菌药物和消毒剂对假单胞菌外排系统的影响。蛋白质合成抑制剂（氨基糖苷类、四环素、氯霉素等）的亚抑制浓度会诱导MexXY多药外排系统。已知这种反应是由对前导肽PA5471.1翻译的干扰介导的，从而对PA5471基因产物的表达产生影响。此外，在接触亚抑制浓度的消毒剂如洗必泰和苯扎氯铵时，会观察到MexCD-OprJ多药外排系统的诱导。已知这种反应依赖于AlgU应激反应因子。总之，铜绿假单胞菌的这些生物学反应为改进和优化化疗提供了有用的线索，以便在适当治疗假单胞菌感染的同时尽量减少耐药性出现。
