Maron Bar, Zanchi Caroline, Johnston Paul, Rolff Jens, Friedman Jonathan, Hayouka Zvi
Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot, Israel.
Institute of Environmental Sciences, The Hebrew University of Jerusalem, Rehovot, Israel.
iScience. 2025 May 14;28(6):112671. doi: 10.1016/j.isci.2025.112671. eCollection 2025 Jun 20.
Antimicrobial resistance (AMR) poses a critical global health challenge, prompting the exploration of antimicrobial peptides (AMPs) as alternatives. Here, we investigated the genetic mechanisms of resistance evolution in against single and combined AMPs (temporin, melittin, and pexiganan). Whole-genome sequencing of evolved populations revealed that combination therapy significantly reduced the overall number of mutations, and importantly, did not typically lead to broad multi-AMP resistance. Instead, resistance likely focused on one component of the combination. While mutations in (toxin transport) and (wall-teichoic acid biosynthesis) were common across treatments, AMP-specific mutations, such as and , were also identified. Notably, mutations in a hypothetical membrane protein operon (SAOUHSC_02307-02309) imply a potential pexiganan resistance pathway. The findings suggest that AMP combinations might limit mutation accumulation, while constraining the development of general AMP resistance. The genetic mechanism of resistance is complex, thus careful selection is required for designing effective AMP-based therapies.
抗菌耐药性（AMR）对全球健康构成了严峻挑战，促使人们探索抗菌肽（AMPs）作为替代方案。在此，我们研究了[具体对象]对单一和联合抗菌肽（天蚕素、蜂毒肽和pexiganan）耐药性进化的遗传机制。进化群体的全基因组测序表明，联合治疗显著减少了突变的总数，重要的是，通常不会导致广泛的多抗菌肽耐药性。相反，耐药性可能集中在联合治疗的一个成分上。虽然[相关基因]（毒素转运）和[相关基因]（壁磷壁酸生物合成）中的突变在各种治疗中都很常见，但也发现了特定于抗菌肽的突变，如[具体基因]和[具体基因]。值得注意的是，一个假定的膜蛋白操纵子（SAOUHSC_02307 - 02309）中的突变暗示了一种潜在的pexiganan耐药途径。研究结果表明，抗菌肽联合使用可能会限制突变积累，同时抑制一般抗菌肽耐药性的发展。耐药性的遗传机制很复杂，因此在设计基于抗菌肽的有效疗法时需要谨慎选择。
