Bonacorsi Andrea, Trespidi Gabriele, Scoffone Viola C, Irudal Samuele, Barbieri Giulia, Riabova Olga, Monakhova Natalia, Makarov Vadim, Buroni Silvia
Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, Italy.
Research Center of Biotechnology RAS, Moscow, Russia.
Front Microbiol. 2024 Feb 16;15:1357708. doi: 10.3389/fmicb.2024.1357708. eCollection 2024.
is a major human pathogen, able to establish difficult-to-treat infections in immunocompromised and people with cystic fibrosis (CF). The high rate of antibiotic treatment failure is due to its notorious drug resistance, often mediated by the formation of persistent biofilms. Alternative strategies, capable of overcoming resistance, include antivirulence compounds which impair bacterial pathogenesis without exerting a strong selective pressure, and the use of antimicrobial adjuvants that can resensitize drug-resistant bacteria to specific antibiotics. In this work, the dispirotripiperazine derivative PDSTP, already studied as antiviral, was characterized for its activity against adhesion to epithelial cells, its antibiotic adjuvant ability and its biofilm inhibitory potential. PDSTP was effective in impairing the adhesion of to various immortalized cell lines. Moreover, the combination of clinically relevant antibiotics with the compound led to a remarkable enhancement of the antibiotic efficacy towards multidrug-resistant clinical strains. PDSTP-ceftazidime combination maintained its efficacy in a infection model. Finally, the compound showed a promising biofilm inhibitory activity at low concentrations when tested both and using an pig lung model. Altogether, these results validate PDSTP as a promising compound, combining the ability to decrease virulence by impairing its adhesion and biofilm formation, with the capability to increase antibiotic efficacy against antibiotic resistant strains.
是一种主要的人类病原体，能够在免疫功能低下者和囊性纤维化（CF）患者中引发难以治疗的感染。抗生素治疗失败率高是由于其臭名昭著的耐药性，这通常由持续性生物膜的形成介导。能够克服耐药性的替代策略包括不施加强大选择压力就能损害细菌致病性的抗毒力化合物，以及能使耐药细菌对特定抗生素重新敏感的抗菌佐剂的使用。在这项工作中，已作为抗病毒药物研究过的双螺哌嗪衍生物PDSTP，对其针对上皮细胞的黏附活性、抗生素佐剂能力及其生物膜抑制潜力进行了表征。PDSTP能有效损害其对各种永生化细胞系的黏附。此外，临床相关抗生素与该化合物的组合显著增强了抗生素对多重耐药临床菌株的疗效。PDSTP-头孢他啶组合在感染模型中保持了其疗效。最后，当在体外和使用猪肺模型进行测试时，该化合物在低浓度下显示出有前景的生物膜抑制活性。总之，这些结果证实PDSTP是一种有前景的化合物，它兼具通过损害其黏附和生物膜形成来降低毒力的能力，以及增强对抗生素耐药菌株的抗生素疗效的能力。
