Antibacterials Research Unit, Pfizer Worldwide Research & Development, Groton, CT, USA.
Antimicrob Agents Chemother. 2012 Dec;56(12):6334-42. doi: 10.1128/AAC.01345-12. Epub 2012 Oct 1.
The incidence of hospital-acquired infections with multidrug-resistant (MDR) Gram-negative pathogens is increasing at an alarming rate. Equally alarming is the overall lack of efficacious therapeutic options for clinicians, which is due primarily to the acquisition and development of various antibiotic resistance mechanisms that render these drugs ineffective. Among these mechanisms is the reduced permeability of the outer membrane, which prevents many marketed antibiotics from traversing this barrier. To circumvent this, recent drug discovery efforts have focused on conjugating a siderophore moiety to a pharmacologically active compound that has been designed to hijack the bacterial siderophore transport system and trick cells into importing the active drug by recognizing it as a nutritionally beneficial compound. MC-1, a novel siderophore-conjugated β-lactam that promotes its own uptake into bacteria, has exquisite activity against many Gram-negative pathogens. While the inclusion of the siderophore was originally designed to facilitate outer membrane penetration into Gram-negative cells, here we show that this structural moiety also renders other clinically relevant antibiotic resistance mechanisms unable to affect MC-1 efficacy. Resistance frequency determinations and subsequent characterization of first-step resistant mutants identified PiuA, a TonB-dependent outer membrane siderophore receptor, as the primary means of MC-1 entry into Pseudomonas aeruginosa. While the MICs of these mutants were increased 32-fold relative to the parental strain in vitro, we show that this resistance phenotype is not relevant in vivo, as alternative siderophore-mediated uptake mechanisms compensated for the loss of PiuA under iron-limiting conditions.
耐多药（MDR）革兰氏阴性病原体引起的医院获得性感染的发病率正在以惊人的速度增长。同样令人震惊的是，临床医生总体上缺乏有效的治疗选择，这主要是由于各种抗生素耐药机制的获得和发展，使这些药物无效。其中一种机制是外膜的通透性降低，这阻止了许多市售抗生素穿越这一障碍。为了解决这个问题，最近的药物发现工作集中在将一个铁载体部分与一种药理学上有效的化合物结合上，这种化合物被设计用来劫持细菌的铁载体转运系统，并通过识别它作为一种有益的营养化合物来欺骗细胞导入活性药物。MC-1 是一种新型的铁载体结合的β-内酰胺抗生素，它可以促进自身被细菌摄取，对许多革兰氏阴性病原体具有极好的活性。虽然铁载体的包含最初是为了促进外膜穿透革兰氏阴性细胞，但在这里我们表明，这种结构部分也使其他临床相关的抗生素耐药机制无法影响 MC-1 的疗效。耐药频率测定和随后对第一步耐药突变体的特征分析表明，PiuA 是一种依赖 TonB 的外膜铁载体受体，是 MC-1 进入铜绿假单胞菌的主要途径。虽然这些突变体的 MIC 比亲本菌株在体外增加了 32 倍，但我们表明，这种耐药表型在体内并不相关，因为替代的铁载体介导的摄取机制在铁限制条件下补偿了 PiuA 的缺失。
