Proguanil and chlorhexidine augment the antibacterial activities of clarithromycin and rifampicin againstAcinetobacter baumannii

Abstract

ABSTRACTThe emergence ofAcinetobacter baumanniiinfections as a significant healthcare concern in hospital settings, coupled with their association with poorer clinical outcomes, has prompted extensive investigation into novel therapeutic agents and innovative treatment strategies. Proguanil and chlorhexidine, both categorized as biguanide compounds, have displayed clinical efficacy as antimalarial and topical antibacterial agents, respectively. In this study, we conducted an investigation to assess the effectiveness of combining proguanil and chlorhexidine with clarithromycin or rifampicin against both laboratory strains and clinical isolates ofA. baumannii. The combination therapy demonstrated rapid bactericidal activity against planktonic multidrug-resistantA. baumannii, exhibiting efficacy in eradicating mature biofilms and impeding the development of antibiotic resistancein vitro. Additionally, when administered in conjunction with clarithromycin or rifampicin, proguanil enhanced the survival rate of mice afflicted with intraperitonealA. baumanniiinfections, and chlorhexidine expedited wound healing in mice with skin infections. These findings are likely attributable to the disruption ofA. baumanniicell membrane integrity by proguanil and chlorhexidine, resulting in heightened membrane permeability and enhanced intracellular accumulation of clarithromycin and rifampicin. Overall, this study underscores the potential of employing proguanil and chlorhexidine in combination with specific antibiotics to effectively combatA. baumanniiinfections and improve treatment outcomes in clinically challenging scenarios.IMPORTANCEA. baumanniihas emerged as a globally significant nosocomial pathogen due to its remarkable ability to acquire antibiotic resistance and develop biofilms on both biotic and abiotic surfaces. Recent research has demonstrated that the antidiabetic drug metformin has a potentiation effect on doxycycline and minocycline against certain multidrug-resistant bacterial pathogens, suggesting the potential of this biguanide agent as a novel tetracyclines adjuvant. In this study, we provide evidence showing that the combination of proguanil and chlorhexidine with clarithromycin or rifampicin exhibits rapid bactericidal activities against both planktonic cells and mature biofilms ofA. baumannii, the capacity to inhibit the development of antibiotic resistance and improvement of the treatment outcomes inA. baumannii-infected mice. Given the advantages of repurposing non-antibiotic drugs as antibiotic adjuvants, proguanil and chlorhexidine show promise as adjuvants of specific antibiotics in combating clinically significant pathogenicA. baumannii.