CNRS, Aix-Marseille Univ, LISM UMR7255, IMM FR3479, Marseille, France.
Aix Marseille Univ, CNRS, Centrale Marseille, iSm2 (UMR7313), Marseille, France.
J Biomed Sci. 2024 Jan 29;31(1):18. doi: 10.1186/s12929-024-01007-8.
Mycobacterium abscessus, a fast-growing non-tuberculous mycobacterium, is an emerging opportunistic pathogen responsible for chronic bronchopulmonary infections in people with respiratory diseases such as cystic fibrosis (CF). Due to its intrinsic polyresistance to a wide range of antibiotics, most treatments for M. abscessus pulmonary infections are poorly effective. In this context, antimicrobial peptides (AMPs) active against bacterial strains and less prompt to cause resistance, represent a good alternative to conventional antibiotics. Herein, we evaluated the effect of three arenicin isoforms, possessing two or four Cysteines involved in one (Ar-1, Ar-2) or two disulfide bonds (Ar-3), on the in vitro growth of M. abscessus.
The respective disulfide-free AMPs, were built by replacing the Cysteines with alpha-amino-n-butyric acid (Abu) residue. We evaluated the efficiency of the eight arenicin derivatives through their antimicrobial activity against M. abscessus strains, their cytotoxicity towards human cell lines, and their hemolytic activity on human erythrocytes. The mechanism of action of the Ar-1 peptide was further investigated through membrane permeabilization assay, electron microscopy, lipid insertion assay via surface pressure measurement, and the induction of resistance assay.
Our results demonstrated that Ar-1 was the safest peptide with no toxicity towards human cells and no hemolytic activity, and the most active against M. abscessus growth. Ar-1 acts by insertion into mycobacterial lipids, resulting in a rapid membranolytic effect that kills M. abscessus without induction of resistance.
Overall, the present study emphasized Ar-1 as a potential new alternative to conventional antibiotics in the treatment of CF-associated bacterial infection related to M. abscessus.
脓肿分枝杆菌是一种快速生长的非结核分枝杆菌，是一种新兴的机会性病原体，可导致囊性纤维化（CF）等呼吸道疾病患者发生慢性支气管肺部感染。由于其对广泛抗生素固有耐药性，大多数脓肿分枝杆菌肺部感染的治疗效果不佳。在这种情况下，针对细菌菌株具有活性且不太可能引起耐药性的抗菌肽（AMPs），是对抗生素的良好替代。在此，我们评估了三种天蚕素异构体的效果，这三种天蚕素异构体分别含有两个或四个半胱氨酸，涉及一个（Ar-1、Ar-2）或两个二硫键（Ar-3），以评估它们对体外生长的脓肿分枝杆菌的影响。
通过用α-氨基丁酸（Abu）残基取代半胱氨酸，构建了各自无二硫键的 AMPs。我们通过评估八种天蚕素衍生物对脓肿分枝杆菌菌株的抗菌活性、对人细胞系的细胞毒性以及对人红细胞的溶血活性，来评估它们的效率。通过膜通透性测定、电子显微镜、通过表面压力测量的脂质插入测定以及耐药诱导测定，进一步研究了 Ar-1 肽的作用机制。
结果表明，Ar-1 是最安全的肽，对人细胞没有毒性，没有溶血活性，对脓肿分枝杆菌的生长最具活性。Ar-1 通过插入分枝杆菌脂质发挥作用，导致快速的膜溶解作用，杀死脓肿分枝杆菌而不会诱导耐药性。
总体而言，本研究强调了 Ar-1 作为一种有潜力的新型抗生素替代物，可用于治疗与脓肿分枝杆菌相关的 CF 相关细菌感染。
