Oglesby-Sherrouse Amanda G, Djapgne Louise, Nguyen Angela T, Vasil Adriana I, Vasil Michael L
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA; Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, MD, USA.
Pathog Dis. 2014 Apr;70(3):307-20. doi: 10.1111/2049-632X.12132. Epub 2014 Feb 10.
Pseudomonas aeruginosa is a Gram-negative opportunistic bacterial pathogen that is refractory to a variety of current antimicrobial therapeutic regimens. Complicating treatment for such infections is the ability of P. aeruginosa to form biofilms, as well as several innate and acquired resistance mechanisms. Previous studies suggest iron plays a role in resistance to antimicrobial therapy, including the efficacy of an FDA-approved iron chelator, deferasirox (DSX), or Gallium, an iron analog, in potentiating antibiotic-dependent killing of P. aeruginosa biofilms. Here, we show that iron-replete conditions enhance resistance of P. aeruginosa nonbiofilm growth against tobramycin and tigecycline. Interestingly, the mechanism of iron-enhanced resistance to each of these antibiotics is distinct. Whereas pyoverdine-mediated iron uptake is important for optimal resistance to tigecycline, it does not enhance tobramycin resistance. In contrast, heme supplementation results in increased tobramycin resistance, while having no significant effect on tigecycline resistance. Thus, nonsiderophore bound iron plays an important role in resistance to tobramycin, while pyoverdine increases the ability of P. aeruginosa to resist tigecycline treatment. Lastly, we show that iron increases the minimal concentration of tobramycin, but not tigecycline, required to eradicate P. aeruginosa biofilms. Moreover, iron depletion blocks the previous observed induction of biofilm formation by subinhibitory concentrations of tobramycin, suggesting iron and tobramycin signal through overlapping regulatory pathways to affect biofilm formation. These data further support the role of iron in P. aeruginosa antibiotic resistance, providing yet another compelling case for targeting iron acquisition for future antimicrobial drug development.
铜绿假单胞菌是一种革兰氏阴性机会性细菌病原体，对目前的多种抗菌治疗方案具有耐药性。铜绿假单胞菌形成生物膜的能力以及几种先天性和获得性耐药机制使此类感染的治疗变得复杂。先前的研究表明，铁在对抗菌治疗的耐药性中起作用，包括美国食品药品监督管理局（FDA）批准的铁螯合剂地拉罗司（DSX）或铁类似物镓在增强抗生素依赖性杀灭铜绿假单胞菌生物膜方面的功效。在此，我们表明富铁条件增强了铜绿假单胞菌非生物膜生长对妥布霉素和替加环素的耐药性。有趣的是，铁增强对每种抗生素耐药性的机制是不同的。虽然绿脓菌素介导的铁摄取对于对替加环素的最佳耐药性很重要，但它不会增强对妥布霉素的耐药性。相比之下，补充血红素会导致妥布霉素耐药性增加，而对替加环素耐药性没有显著影响。因此，非铁载体结合铁在对妥布霉素的耐药性中起重要作用，而绿脓菌素增加了铜绿假单胞菌抵抗替加环素治疗的能力。最后，我们表明铁增加了根除铜绿假单胞菌生物膜所需的妥布霉素的最低浓度，但不是替加环素的最低浓度。此外，铁耗竭阻止了先前观察到的亚抑菌浓度妥布霉素诱导生物膜形成，这表明铁和妥布霉素通过重叠的调节途径发出信号以影响生物膜形成。这些数据进一步支持了铁在铜绿假单胞菌抗生素耐药性中的作用，为未来抗菌药物开发靶向铁摄取提供了另一个令人信服的案例。
