Mitoxantrone targets both host and bacteria to overcome vancomycin resistance in Enterococcus faecalis

Summary:

Antibiotic resistance critically limits treatment options for infection caused by opportunistic pathogens such as enterococci. Here, the authors led by GCIR member Professor Kimberly Kline, investigate the antibiotic and immunological activity of the anticancer agent mitoxantrone (MTX) in vitro and in vivo against vancomycin-resistant Enterococcus faecalis (VRE). They show that, in vitro, MTX is a potent antibiotic against Gram-positive bacteria through induction of reactive oxygen species and DNA damage. MTX also synergizes with vancomycin against VRE, rendering the resistant strains more permeable to MTX. In a murine wound infection model, single-dose MTX treatment effectively reduces VRE numbers, with further reduction when combined with vancomycin. Multiple MTX treatments accelerate wound closure. 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. These results show that MTX represents a promising bacterium- and host-targeted therapeutic for overcoming vancomycin resistance.

Full article: https://www.science.org/doi/10.1126/sciadv.add9280

Why is it important?

Antibiotic resistance represents a major threat to global health. Recent estimates attribute nearly 5 million deaths in 2019 to antimicrobial resistance, and this figure is projected to rise to 10 million deaths annually by 2050. Therefore, multiple treatment approaches, with antimicrobials that overcome existing resistance mechanisms and adjuvant host-directed therapies that enhance natural immune responses, are emerging as important alternatives to combat bacterial infections.

Enterococcus faecalis, Staphylococcus aureus and Pseudomonas are among the bacterial species most frequently isolated from wounds such as burns, diabetic foot ulcers, surgical sites and chronic wounds.

A potential target of host-directed immunotherapy is to promote macrophage clearance of enterococci. Because of their plasticity and critical role in infection control and tissue repair, drugs that can reprogram macrophages for optimal response may improve infection outcomes.

From a pool of 4126 compounds, the authors previously identified a series of drugs capable of reprogramming macrophages into a pro- or anti-inflammatory state. In this study, the authors assessed the antibiotic activity and macrophage enhancement of selected compounds, leading to enhanced bacterial killing. They concluded that mitoxantrone (MTX), an antineoplastic agent commonly used to treat acute leukaemia, prostate and breast cancers, as well as multiple sclerosis by disrupting DNA replication in mammalian cells, is both antimicrobial and immunomodulatory. Data show that MTX resensitises vancomycin-resistant Enterococcus faecalis to vancomycin and promotes macrophage recruitment and activation, making MTX an attractive candidate for difficult-to-treat Enterococcus faecalis infections.

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