Krebs Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, UK.
AvidBiotics Corp., South San Francisco, CA 94080, USA.
Sci Transl Med. 2017 Sep 6;9(406). doi: 10.1126/scitranslmed.aah6813.
There is a medical need for antibacterial agents that do not damage the resident gut microbiota or promote the spread of antibiotic resistance. We recently described a prototypic precision bactericidal agent, Av-CD291.2, which selectively kills specific strains and prevents them from colonizing mice. We have since selected two Av-CD291.2-resistant mutants that have a surface (S)-layer-null phenotype due to distinct point mutations in the gene. Using newly identified bacteriophage receptor binding proteins for targeting, we constructed a panel of Avidocin-CDs that kills diverse isolates in an S-layer sequence-dependent manner. In addition to bacteriophage receptor recognition, characterization of the mutants also uncovered important roles for S-layer protein A (SlpA) in sporulation, resistance to innate immunity effectors, and toxin production. Surprisingly, S-layer-null mutants were found to persist in the hamster gut despite a complete attenuation of virulence. These findings suggest antimicrobials targeting virulence factors dispensable for fitness in the host force pathogens to trade virulence for viability and would have clear clinical advantages should resistance emerge. Given their exquisite specificity for the pathogen, Avidocin-CDs have substantial therapeutic potential for the treatment and prevention of infections.
人们需要不会破坏常驻肠道菌群或促进抗生素耐药性传播的抗菌药物。我们最近描述了一种典型的精密杀菌剂 Av-CD291.2，它可以选择性地杀死特定菌株并防止它们在小鼠中定植。此后，我们选择了两种 Av-CD291.2 抗性突变体，由于基因中的不同点突变，它们具有表面 (S)-层缺失表型。使用新鉴定的噬菌体受体结合蛋白进行靶向，我们构建了一组 Avidocin-CDs，它们以 S-层序列依赖性方式杀死不同的 分离株。除了噬菌体受体识别外，对突变体的表征还揭示了 S-层蛋白 A (SlpA) 在孢子形成、对先天免疫效应物的抗性和毒素产生中的重要作用。令人惊讶的是，尽管毒性完全减弱，S-层缺失突变体仍在仓鼠肠道中持续存在。这些发现表明，针对宿主适应性无关的毒力因子的抗菌药物迫使病原体为了生存而牺牲毒力，并且如果出现耐药性，将具有明显的临床优势。鉴于它们对病原体的高度特异性，Avidocin-CDs 具有治疗和预防 感染的巨大治疗潜力。
