Loperamide exerts a direct bactericidal effect against M. tuberculosis , M. bovis , M. terrae and M. smegmatis

Abstract

Significance and Impact of the Study: The increasing number of pulmonary disease cases caused by Mycobacterium tuberculosis complex members, but mainly by non-tuberculous mycobacteria (NTB), poses a challenge for therapeutical management, and new drugs to address it are much needed. This study describes the bactericidal effect of loperamide against tuberculous and NTB in a dose-dependent manner at a concentration suitable for human use. Loperamide is a drug approved by the FDA that may be repurposed as an adjunct therapy to combat mycobacterial infections.

Anti-diarrheal drug loperamide induces dysbiosis in zebrafish microbiota via bacterial inhibition

“…These results were consistent with a previous study in mice, in which loperamide was used to increase gastrointestinal transit time, but also led to alterations in the gut microbial community that were reversible after treatment interruption [58]. This dysbiosis was presumed to result from a reduction of peristaltic movement, but our results suggest that it could also be explained by the loperamide bactericidal activity [27,28].…”

“…In addition to the zebrafish-associated strains studied here, loperamide exhibits bactericidal activity against diverse host-associated microbes including mycobacterial strains (e.g. Mycobacterium tuberculosis) and Staphylococcus aureus, but not Escherichia coli [27,68]. These microbes are members of the human and vertebrate microbiome that may be directly affected by loperamide treatment, resulting in unforeseen microbiota modulation [69].…”

“…It has been suggested that slow transit time and constipation induced by loperamide could be responsible for changes in bacterial composition and decreased diversity observed in rats and mice [23][24][25][26]. Although publications using loperamide to investigate host-associated microbiota establish the link between constipation and microbial dysbiosis, recent studies have identified loperamide hydrochloride and its derivatives as molecules displaying bactericidal activity [27][28][29]. Hence the extent of microbial dysbiosis directly caused by this compound versus its impact on the alteration of host function are poorly understood and ignored in animal models.…”

Improving the treatment of bacterial infections caused by multidrug-resistant bacteria through drug repositioning

“…It is used in the treatment of infectious and non-infectious chronic and acute diarrhea ( Brown, 2015 ; Zhang et al, 2023 ). Due to its mechanism of action, i.e., mediating the intracellular calcium concentration by blocking calcium channels and activating opioid receptors, it is also a candidate for relieving pain, controlling anxiety or reducing insulin resistance ( Juárez et al, 2018 ; Barrientos et al, 2021 ). As an agent with antibacterial potential, loperamide has demonstrated synergism with several classes of antibiotics in the treatment of bacterial infections causing intestinal infections ( in vitro studies).…”

“…Moreover, in vitro tests have demonstrated bactericidal activity against the tuberculous strain M. tuberculosis and the non-tuberculous M. bovis BCG, M. terrae and M. smegmatis . In addition to activating bactericidal mechanisms, this drug also caused an immune response, influencing the activity of macrophages and the inflammatory process ( Juárez et al, 2018 ; Barrientos et al, 2021 ). Research on the antibacterial effect of loperamide is currently in the preclinical phase.…”