An estimated ~30% of health care–associated enterococcal infections are caused by vancomycin-resistant strains, further reducing treatment options ( 9). faecalis have low-level intrinsic resistance to penicillin, ampicillin, and cephalosporins ( 8). Enterococcus faecalis, Staphylococcus aureus, and Pseudomonas are among the most frequently isolated bacterial species from wounds including burns, diabetic foot ulcers, surgical sites, and chronic wounds ( 4– 7). Thus, multipronged treatment approaches, including antimicrobials that overcome existing resistance mechanisms and host-directed adjuvant therapies that enhance natural immune responses, are emerging as important alternatives to fight bacterial infections ( 3).
Recent estimates attribute 4.95 million deaths in 2019 to antimicrobial resistance (AMR) ( 1), with this number predicted to climb to 10 million deaths annually by 2050 ( 2). These results show that MTX represents a promising bacterium- and host-targeted therapeutic for overcoming vancomycin resistance.Īntibiotic resistance represents a major global health threat. MTX also promotes macrophage recruitment and proinflammatory cytokine induction at the wound site and augments intracellular bacterial killing in macrophages by up-regulating the expression of lysosomal enzymes. Multiple MTX treatments accelerate wound closure. In a murine wound infection model, single-dose MTX treatment effectively reduces VRE numbers, with further reduction when combined with vancomycin. MTX also synergizes with vancomycin against VRE, rendering the resistant strains more permeable to MTX. We show that, in vitro, MTX is a potent antibiotic against Gram-positive bacteria through induction of reactive oxygen species and DNA damage. Here, we investigate the antibiotic and immunological activity of the anticancer agent mitoxantrone (MTX) in vitro and in vivo against vancomycin-resistant Enterococcus faecalis (VRE). Antibiotic resistance critically limits treatment options for infection caused by opportunistic pathogens such as enterococci.
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