Galdino Anna Clara M, Vaillancourt Mylene, Celedonio Diana, Huse Kara, Doi Yohei, Lee Janet S, Jorth Peter
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048 USA.
Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Res Sq. 2023 May 18:rs.3.rs-2644953. doi: 10.21203/rs.3.rs-2644953/v1.
Antibiotic cross-protection enables resistant bacteria to protect other bacteria that would be otherwise susceptible to the drug. Cefiderocol is the first siderophore cephalosporin antibiotic approved for treating Gram-negative bacterial infections, including carbapenem-resistant strains. While highly effective, CFDC resistance has been detected clinically, and mechanisms of resistance and cross-protection are not completely understood. In this study, we used experimental evolution and whole genome sequencing to identify cefiderocol resistance mechanisms and evaluated the trade-offs of evolving resistance. We found some cefiderocol-resistant populations evolved cross-protective social behavior, preventing cefiderocol killing of susceptible siblings. Notably, cross-protection was driven by increased secretion of bacterial iron-binding siderophores, which is unique from previously described antibiotic degradation mediated cross-protection. While concerning, we also showed that resistance can be selected against in drug-free environments. Deciphering the costs associated with antibiotic resistance might aid the development of evolution-informed therapeutic approaches to delay the evolution of antibiotic resistance.
抗生素交叉保护使耐药细菌能够保护其他原本对该药物敏感的细菌。头孢地尔是首个被批准用于治疗革兰氏阴性菌感染（包括耐碳青霉烯类菌株）的铁载体头孢菌素抗生素。虽然它非常有效，但临床上已检测到对头孢地尔的耐药性，且耐药性和交叉保护机制尚未完全明确。在本研究中，我们利用实验进化和全基因组测序来确定头孢地尔的耐药机制，并评估进化出耐药性的权衡。我们发现一些耐头孢地尔的群体进化出了交叉保护的社会行为，阻止头孢地尔杀死敏感的同胞细菌。值得注意的是，交叉保护是由细菌铁结合铁载体分泌增加所驱动的，这与先前描述的抗生素降解介导的交叉保护不同。尽管令人担忧，但我们也表明在无药物环境中可以选择对抗耐药性。解读与抗生素耐药性相关的代价可能有助于开发基于进化的治疗方法，以延缓抗生素耐药性的进化。
