Andrade Mariana, Neves Joana, Bento Maria, Marques Joana, Seabra Sofia G, Silveira Henrique, Rodrigues Liliana, Armada Ana, Viveiros Miguel, Couto Isabel, Costa Sofia Santos
Global Health and Tropical Medicine, GHTM, Associated Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, 1349-008 Lisbon, Portugal.
Antibiotics (Basel). 2025 Feb 11;14(2):183. doi: 10.3390/antibiotics14020183.
Antimicrobial-resistant is a growing threat to human health for which alternative therapeutic options are needed. In this study, we aimed to evaluate the efficacy of amlodipine (AML) and imipramine (IMI) to treat infection in the larval model by targeting efflux and biofilms, which are relevant contributors to antimicrobial resistance and virulence in . In-house reared were used in virulence assays to determine the infective dose of two strains differing in the expression of (gene encoding the native NorA efflux pump). Toxicology assays were conducted to determine the drugs' LD for . Drug efficacy assays were performed to evaluate the potential of amlodipine, imipramine and the control drugs ciprofloxacin (CIP) and enalapril (ENA) to clear infection in . Survival analysis defined the infective dose as 1 × 10 CFU/larva for both strains. High LD values were determined (CIP: >1000 mg/kg; AML: >640 mg/kg; IMI: 1141 mg/kg; ENA: >1280 mg/kg), revealing a high tolerance of to these drugs. AML at 15 mg/kg and IMI at 100 mg/kg increased the larvae survival by 20% ( = 0.04) and 11% ( = 0.11), respectively, also positively affecting health score indexes. In agreement with the literature, ciprofloxacin at >100 mg/kg promoted larvae survival by >73%. Amlodipine and imipramine show mild potential as new therapeutic options for managing infections but are promising as new lead molecules. This study also reinforces as a sustainable, reliable model for drug evaluation.
抗菌耐药性对人类健康构成了日益严重的威胁，因此需要替代性治疗方案。在本研究中，我们旨在评估氨氯地平（AML）和丙咪嗪（IMI）通过靶向外排和生物膜来治疗幼虫模型中感染的疗效，外排和生物膜是抗菌耐药性和毒力的相关促成因素。在毒力试验中使用内部饲养的幼虫来确定两种表达不同（编码天然NorA外排泵的基因）的菌株的感染剂量。进行毒理学试验以确定药物对幼虫的半数致死量（LD）。进行药物疗效试验以评估氨氯地平、丙咪嗪以及对照药物环丙沙星（CIP）和依那普利（ENA）清除幼虫感染的潜力。生存分析将两种菌株的感染剂量定义为1×10 CFU/幼虫。确定了较高的半数致死量值（CIP：>1000 mg/kg；AML：>640 mg/kg；IMI：1141 mg/kg；ENA：>1280 mg/kg），表明幼虫对这些药物具有高耐受性。15 mg/kg的AML和100 mg/kg的IMI分别使幼虫存活率提高了20%（P = 0.04）和11%（P = 0.11），对健康评分指标也有积极影响。与文献一致，>100 mg/kg的环丙沙星使幼虫存活率提高>73%。氨氯地平和丙咪嗪作为管理感染的新治疗选择显示出温和的潜力，但作为新的先导分子很有前景。本研究还强化了幼虫作为药物评估的可持续、可靠模型的作用。
