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This study aimed to evaluate the potential of tamoxifen and N-desmethyltamoxifen metabolites as therapeutic agents against multidrug-resistant <i>Escherichia coli</i> and <i>Acinetobacter baumannii,</i> using a repurposing approach to shorten the time required to obtain a new effective treatment against multidrug-resistant bacterial infections. Characterisation and virulence studies were conducted on <i>E. coli</i> (colistin-susceptible C1-7-LE and colistin-resistant MCR-1+) and <i>A. baumannii</i> (tigecycline-susceptible Ab#9 and tigecycline-resistant Ab#186) strains. The efficacy of the metabolite mix (33.3% each) and N-desmethyltamoxifen in combination with colistimethate sodium (CMS) or tigecycline was evaluated in experimental models in mice. In the pneumonia model, N-desmethyltamoxifen exhibited significant efficacy against Ab#9 and both <i>E. coli</i> strains, especially <i>E. coli</i> MCR-1+ (−2.86 log₁₀ CFU/g lungs, −5.88 log₁₀ CFU/mL blood, and −50% mortality), and against the Ab#186 strain when combined with CMS (−2.27 log₁₀ CFU/g lungs, −2.73 log₁₀ CFU/mL blood, and −40% mortality) or tigecycline (−3.27 log₁₀ CFU/g lungs, −4.95 log₁₀ CFU/mL blood, and −50% mortality). Moreover, the metabolite mix in combination with both antibiotics decreased the bacterial concentrations in the lungs and blood for both <i>A. baumannii</i> strains. In the sepsis model, the significant efficacy of the metabolite mix was restricted to the colistin-susceptible <i>E. coli</i> C1-7-LE strain (−3.32 log₁₀ CFU/g lung, −6.06 log₁₀ CFU/mL blood, and −79% mortality). N-desmethyltamoxifen could be a new therapeutic option in combination with CMS or tigecycline for combating multidrug-resistant GNB, specifically <i>A. baumannii</i>.