posted on 2024-01-06, 18:29authored byJingru Shi, Chen Chen, Miao Zhang, Zhiqiang Wang, Yuan Liu
The
escalating mortality rate resulting from multidrug-resistant
(MDR) bacteria has intensified the urgency for innovative antimicrobial
agents. Currently, the antimicrobial activity of compounds is usually
assessed by testing the minimum inhibitory concentration (MIC) on
a standardized laboratory medium. However, such screening conditions
differ from the in vivo environment, making it easy to overlook some
antibacterial agents that are active in vivo but less active in vitro.
Herein, by using tissue medium RPMI, we uncover that anthracyclines,
especially mitoxantrone (MX), exhibit improved bacteriostatic and
bactericidal effects against various MDR bacteria in host-like media.
Transcriptome results reveal that LPS modification-related genes of
bacterial membrane surfaces and metabolic genes are significantly
down-regulated in RPMI media. Mechanistic studies demonstrate that
MX leads to more substantial membrane damage, increased ROS production,
and DNA damage in host-mimicking conditions. Furthermore, we demonstrate
that MX and colistin exhibit strong synergistic effects against mcr-positive strains in host-mimicking media by disrupting
iron homeostasis. In an experimental murine infection model, MX monotreatment
demonstrates therapeutic efficacy in reducing bacterial burdens. Overall,
our work suggests that mimicking the host condition is an effective
strategy to identify new antimicrobial agents and highlights the therapeutic
potential of anthracycline drugs in combating MDR pathogens.