Clinical Microbiology and Bioactive Screening Laboratory, Council of Scientific and Industrial Research - Institute of Microbial Technology, Chandigarh, India.
Clinical Microbiology and Bioactive Screening Laboratory, Council of Scientific and Industrial Research - Institute of Microbial Technology, Chandigarh, India.
Int J Antimicrob Agents. 2019 Jun;53(6):838-843. doi: 10.1016/j.ijantimicag.2019.03.020. Epub 2019 Mar 28.
The alarming burden of antibiotic resistance in nosocomial pathogens warrants the discovery and development of new and effective antimicrobial compounds. Small cationic antimicrobial peptides seem to be a promising therapeutic alternative to fight multi-drug resistance. This study investigated the in-vitro potential of a previously reported lantibiotic, paenibacillin, from the clinical perspective. An antimicrobial peptide, M152-P4, was isolated, purified and characterized from a mud isolate, and its susceptibility was determined in clinical isolates of Staphylococcus aureus and Enterococcus spp. Time-kill kinetics, resistance, probable mode of action, haemolytic activity and mammalian cytotoxicity were investigated. M152-P4 was identified as paenibacillin based on mass spectroscopy data, amino acid analysis and biosynthetic gene cluster analysis. It had potent antibacterial activity against the Gram-positive pathogens tested, with minimum inhibitory concentrations from 0.1 to 1.56 µM. It appeared very challenging for S. aureus to develop resistance to this compound. Also, paenibacillin penetrated the outer layer of bacteria, and depolarized the membrane completely by creating pores in the plasma membrane with better potential than nisin. Paenibacillin showed no haemolysis up to 60 µM, and the half maximal inhibitory concentration on mammalian cell lines was >100 µM. These results highlight the excellent antibacterial properties of paenibacillin in clinically relevant pathogens. It is stable in the presence of serum, and non-haemolytic and non-cytotoxic even above the therapeutic concentration. Further research efforts regarding toxicity and in-vivo efficacy are necessary to develop paenibacillin as a next-generation therapeutic drug to overcome multi-drug resistance in Gram-positive pathogens.
耐抗生素的医院病原体的惊人负担需要发现和开发新的和有效的抗菌化合物。小阳离子抗菌肽似乎是一种有前途的治疗选择，可以对抗多药耐药性。这项研究从临床角度研究了一种先前报道的来自粘细菌的抗生素，即培尼西林的体外潜力。从泥样分离物中分离、纯化和表征了一种抗菌肽 M152-P4，并测定了其对金黄色葡萄球菌和肠球菌属临床分离株的敏感性。测定了时间杀伤动力学、耐药性、可能的作用模式、溶血活性和哺乳动物细胞毒性。根据质谱数据、氨基酸分析和生物合成基因簇分析，M152-P4 被鉴定为培尼西林。它对测试的革兰氏阳性病原体具有很强的抗菌活性，最低抑菌浓度为 0.1 至 1.56 µM。金黄色葡萄球菌似乎很难对这种化合物产生耐药性。此外，培尼西林穿透细菌的外层，并通过在质膜上形成孔完全去极化膜，其潜力优于乳链菌肽。培尼西林的溶血率在 60 µM 以下，对哺乳动物细胞系的半数最大抑制浓度>100 µM。这些结果突出了培尼西林在临床相关病原体中具有出色的抗菌特性。它在存在血清时稳定，即使在治疗浓度以上也不溶血且无细胞毒性。需要进一步研究毒性和体内疗效，以开发培尼西林作为下一代治疗药物，以克服革兰氏阳性病原体的多药耐药性。
