Efficacy of Tamoxifen Metabolites in Combination with Colistin and Tigecycline in Experimental Murine Models of and .

This study aimed to evaluate the potential of tamoxifen and N-desmethyltamoxifen metabolites as therapeutic agents against multidrug-resistant and 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 (colistin-susceptible C1-7-LE and colistin-resistant MCR-1+) and (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 strains, especially MCR-1+ (-2.86 log CFU/g lungs, -5.88 log CFU/mL blood, and -50% mortality), and against the Ab#186 strain when combined with CMS (-2.27 log CFU/g lungs, -2.73 log CFU/mL blood, and -40% mortality) or tigecycline (-3.27 log CFU/g lungs, -4.95 log 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 strains. In the sepsis model, the significant efficacy of the metabolite mix was restricted to the colistin-susceptible C1-7-LE strain (-3.32 log CFU/g lung, -6.06 log 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 .