Abstract
Recently, a novel efflux pump gene cluster called tmexCD1-toprJ1 and its variants have been identified, which undermine the antibacterial activity of tigecycline, one of the last remaining options effective against multidrug-resistant (MDR) Gram-negative bacteria. Herein, we report the potent synergistic effect of the non-steroidal anti-inflammatory drug benzydamine in combination with tigecycline at sub-inhibitory concentrations against various temxCD-toprJ-positive Gram-negative pathogens. The combination of benzydamine and tigecycline killed all drug-resistant pathogens during 24 h of incubation. In addition, the evolution of tigecycline resistance was significantly suppressed in the presence of benzydamine. Studies on the mechanisms of synergism showed that benzydamine disrupted the bacterial proton motive force and the functionality of this kind of novel plasmid-encoded resistance-nodulation-division efflux pump, thereby promoting the intracellular accumulation of tigecycline. Most importantly, the combination therapy of benzydamine and tigecycline effectively improved the survival of Galleria mellonella larvae compared to tigecycline monotherapy. Our findings provide a promising drug combination therapeutic strategy for combating superbugs carrying the tmexCD-toprJ gene.
Highlights
Accepted: 2 September 2021Antibiotic resistance mediated by chromosome mutation or horizontal gene transfer constitutes a global threat to public health [1,2]
To test the synergistic activity of BEN and TIG against TMexCD-TOprJ-positive pathogens, a collection of 12 clinical isolates of K. pneumoniae carrying a tmexCD1-toprJ1bearing plasmid and two isolates of P. mirabilis carrying the chromosomal tmexCD3toprJ3 gene cluster, isolated from swine fecal samples taken in Jiangsu Province, were utilized [16]
The results showed that the Minimum inhibitory concentrations (MICs) for BEN were 500 μg/mL in K. pneumoniae and 2000 μg/mL
Summary
Antibiotic resistance mediated by chromosome mutation or horizontal gene transfer constitutes a global threat to public health [1,2]. The emergence of carbapenemresistant enterobacteriaceae (CRE) and MCR-producing enterobacterales (MCRPE) has aggravated the resistance crisis and leaves clinicians few choices from the existing antibiotic pipeline [3,4]. The identification and prevalence of plasmid-mediated tet(X3/X4) [7] and the RND (resistancenodulation-division) efflux pump gene cluster, tmexCD1-toprJ1 [8,9], in clinically important pathogens are undermining the efficacy of TIG in clinical practice. The tet(X3/X4) gene-encoded tetracycline-inactivating enzymes can confer high levels of TIG resistance to bacteria and are even able to inactivate all tetracyclines [12]
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