Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Michael G. DeGroote Institute of Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
mBio. 2020 Sep 22;11(5):e01615-20. doi: 10.1128/mBio.01615-20.
Disruption of the outer membrane (OM) barrier allows for the entry of otherwise inactive antimicrobials into Gram-negative pathogens. Numerous efforts to implement this approach have identified a large number of OM perturbants that sensitize Gram-negative bacteria to many clinically available Gram-positive active antibiotics. However, there is a dearth of investigation into the strengths and limitations of this therapeutic strategy, with an overwhelming focus on characterization of individual potentiator molecules. Herein, we look to explore the utility of exploiting OM perturbation to sensitize Gram-negative pathogens to otherwise inactive antimicrobials. We identify the ability of OM disruption to change the rules of Gram-negative entry, overcome preexisting and spontaneous resistance, and impact biofilm formation. Disruption of the OM expands the threshold of hydrophobicity compatible with Gram-negative activity to include hydrophobic molecules. We demonstrate that while resistance to Gram-positive active antibiotics is surprisingly common in Gram-negative pathogens, OM perturbation overcomes many antibiotic inactivation determinants. Further, we find that OM perturbation reduces the rate of spontaneous resistance to rifampicin and impairs biofilm formation. Together, these data suggest that OM disruption overcomes many of the traditional hurdles encountered during antibiotic treatment and is a high priority approach for further development. The spread of antibiotic resistance is an urgent threat to global health that necessitates new therapeutics. Treatments for Gram-negative pathogens are particularly challenging to identify due to the robust outer membrane permeability barrier in these organisms. Recent discovery efforts have attempted to overcome this hurdle by disrupting the outer membrane using chemical perturbants and have yielded several new peptides and small molecules that allow the entry of otherwise inactive antimicrobials. However, a comprehensive investigation into the strengths and limitations of outer membrane perturbants as antibiotic partners is currently lacking. Herein, we interrogate the interaction between outer membrane perturbation and several common impediments to effective antibiotic use. Interestingly, we discover that outer membrane disruption is able to overcome intrinsic, spontaneous, and acquired antibiotic resistance in Gram-negative bacteria, meriting increased attention toward this approach.
破坏外膜 (OM) 屏障可以使原本不活跃的抗菌药物进入革兰氏阴性病原体。为了实现这一目标，人们进行了大量努力，确定了许多 OM 扰动剂，这些扰动剂使革兰氏阴性细菌对许多临床可用的革兰氏阳性活性抗生素敏感。然而，对于这种治疗策略的优势和局限性的研究很少，压倒性的重点是单个增效剂分子的特征。在这里，我们探讨利用 OM 扰动使革兰氏阴性病原体对原本不活跃的抗菌药物敏感的实用性。我们确定了 OM 破坏改变革兰氏阴性菌进入规则的能力，克服了预先存在的和自发的耐药性，并影响生物膜形成。OM 的破坏扩大了与革兰氏阴性活性相容的疏水性的阈值，包括疏水性分子。我们证明，虽然革兰氏阴性病原体对革兰氏阳性活性抗生素的耐药性非常常见，但 OM 扰动克服了许多抗生素失活决定因素。此外，我们发现 OM 扰动降低了利福平自发耐药的速度，并损害了生物膜的形成。这些数据表明，OM 破坏克服了抗生素治疗中遇到的许多传统障碍，是进一步发展的高度优先方法。抗生素耐药性的传播是对全球健康的紧迫威胁，需要新的治疗方法。革兰氏阴性病原体的治疗特别具有挑战性，因为这些生物体具有强大的外膜通透性屏障。最近的发现努力试图通过使用化学扰动剂破坏外膜来克服这一障碍，并产生了几种允许原本不活跃的抗菌药物进入的新肽和小分子。然而，目前缺乏对作为抗生素伙伴的外膜扰动剂的优势和局限性的全面调查。在这里，我们研究了外膜扰动与几种常见的有效抗生素使用障碍之间的相互作用。有趣的是，我们发现外膜破坏能够克服革兰氏阴性细菌的固有、自发和获得性耐药性，这值得对此方法给予更多关注。
