25:T515,The emergence and prevalence of multidrug-resistant (MDR) bacteria particularly Gram-negative bacteria presents a global crisis for human health. Colistin and tigecycline were recognized as the last resort of defenses against MDR Gram-negative pathogens. However, the emergence and prevalence of MCR or Tet(X)-mediated acquired drug resistance drastically impaired their clinical efficacy. It has been suggested that antimicrobial peptides might act a crucial role in combating antibiotic resistant bacteria owing to their multiple modes of action and characteristics that are not prone to developing drug resistance. Herein, we report a safe and stable tryptophan-rich amphiphilic peptide termed WRK-12 with broad-spectrum antibacterial activity against various MDR bacteria, including MRSA, colistin and tigecycline-resistant Escherichia coli. Mechanistical studies showed that WRK-12 killed resistant E. coli through permeabilizing the bacterial membrane, dissipating membrane potential and triggering the production of reactive oxygen species (ROS). Meanwhile, WRK-12 significantly inhibited the formation of an E. coli biofilm in a dose-dependent manner. These findings revealed that amphiphilic peptide WRK-12 is a promising drug candidate in the fight against MDR bacteria.26:T52d,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.

#	Concept	H-Index	Publications	Citations
1	Medicine	1	1	219
2	Microbiology	1	1	219
3	Intestinal Microbiota	1	1	219
4	Obesity	1	1	219
5	Antimicrobial Resistance	1	1	219

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