Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China.
Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China.
mBio. 2024 Oct 16;15(10):e0139324. doi: 10.1128/mbio.01393-24. Epub 2024 Sep 9.
Phage-antibiotic synergy (PAS) represents a superior treatment strategy for pathogen infections with less probability of resistance development. Here, we aim to understand the molecular mechanism by which PAS suppresses resistance in terms of population evolution. A novel hypervirulent (KP) phage H5 was genetically and structurally characterized. The combination of H5 and ceftazidime (CAZ) showed a robust synergistic effect in suppressing resistance emergence. Single-cell Raman analysis showed that the phage-CAZ combination suppressed bacterial metabolic activities, contrasting with the upregulation observed with phage alone. The altered population evolutionary trajectory was found to be responsible for the contrasting metabolic activities under different selective pressures, resulting in pleiotropic effects. A pre-existing point mutation () was exclusively selected by H5, conferring a fitness advantage and up-regulated activity of carbohydrate metabolism, but also causing a trade-off between phage resistance and collateral sensitivity to CAZ. The point mutation was counter-selected by H5-CAZ, inducing various mutations in that imposed evolutionary disadvantages with higher fitness costs, and suppressed carbohydrate metabolic activity. H5 and H5-CAZ treatments resulted in opposite effects on the transcriptional activity of the phosphotransferase system and the ascorbate and aldarate metabolism pathway, suggesting potential targets for phage resistance suppression. Our study reveals a novel mechanism of resistance suppression by PAS, highlighting how the complexity of bacterial adaptation to selective pressures drives treatment outcomes.
Phage-antibiotic synergy (PAS) has been recently proposed as a superior strategy for the treatment of multidrug-resistant pathogens to effectively reduce bacterial load and slow down both phage and antibiotic resistance. However, the underlying mechanisms of resistance suppression by PAS have been poorly and rarely been studied. In this study, we tried to understand how PAS suppresses the emergence of resistance using a hypervirulent (KP) strain and a novel phage H5 in combination with ceftazidime (CAZ) as a model. Our study reveals a novel mechanism by which PAS drives altered evolutionary trajectory of bacterial populations, leading to suppressed emergence of resistance. The findings advance our understanding of how PAS suppresses the emergence of resistance, and are imperative for optimizing the efficacy of phage-antibiotic therapy to further improve clinical outcomes.
噬菌体-抗生素协同作用（PAS）代表了一种治疗病原体感染的优越策略，因为它不太可能产生耐药性。在这里，我们旨在从种群进化的角度理解 PAS 抑制耐药性的分子机制。我们对一种新型的高毒性（KP）噬菌体 H5 进行了遗传和结构表征。H5 与头孢他啶（CAZ）联合使用显示出强大的协同作用，可抑制耐药性的出现。单细胞拉曼分析显示，噬菌体-CAZ 联合抑制了细菌的代谢活性，与单独使用噬菌体时观察到的上调形成对比。不同选择压力下代谢活性的改变被发现是导致种群进化轨迹不同的原因，从而产生多效性效应。一个预先存在的点突变（）被 H5 特异性选择，赋予了适应性优势和碳水化合物代谢活性的上调，但也导致了噬菌体耐药性和对 CAZ 的附带敏感性之间的权衡。H5-CAZ 对选择了，导致 中出现各种突变，这些突变带来了更高的适应性成本的进化劣势，并抑制了碳水化合物代谢活性。H5 和 H5-CAZ 处理对磷酸转移酶系统和抗坏血酸和醛酸盐代谢途径的转录活性产生了相反的影响，这表明了噬菌体耐药性抑制的潜在靶点。我们的研究揭示了 PAS 抑制耐药性的一种新机制，强调了细菌对选择压力的适应复杂性如何影响治疗结果。
噬菌体-抗生素协同作用（PAS）最近被提议作为治疗多药耐药病原体的优越策略，以有效降低细菌负荷并减缓噬菌体和抗生素耐药性的发展。然而，PAS 抑制耐药性的机制仍知之甚少，很少有研究报道。在这项研究中，我们试图使用一种高毒性（KP）菌株和一种新型噬菌体 H5 与头孢他啶（CAZ）联合作为模型，了解 PAS 如何抑制耐药性的出现。我们的研究揭示了 PAS 驱动细菌种群进化轨迹改变从而抑制耐药性出现的新机制。这些发现增进了我们对 PAS 如何抑制耐药性出现的理解，对于优化噬菌体-抗生素治疗的疗效以进一步改善临床结果至关重要。
