Cholesterol-dependent activity of dapsone against non-replicating persistent mycobacteria

Abstract

One-third of the world’s population is estimated to be latently infected with Mycobacterium tuberculosis . This reservoir of bacteria is largely resistant to antimicrobial treatment that often only targets actively replicating mycobacteria, with current treatment for latent infection revolving around inhibiting the resuscitation event rather than preventing or treating latent infection. As a result, antimicrobials that target latent infection often have little to no activity in vivo. Here we report a method of in vitro analysis of physiologically relevant non-replicating persistence (NRP) utilizing cholesterol as the sole carbon source, alongside hypoxia as a driver of Mycobacterium bovis BCG into the NRP state. Using the minimal cholesterol media NRP assay, we observed an increased state of in vitro resistance to front-line anti-tubercular compounds. However, following a phenotypic screen of an approved-drug library, we identified dapsone as a bactericidal active molecule against cholesterol-dependent NRP M. bovis BCG. Through an overexpression trial of probable antimicrobial target enzymes, we further identified FolP2, a non-functional dihydropteroate synthase homologue, as the likely target of dapsone under cholesterol-NRP due to a significant increase in bacterial resistance when overexpressed. These results highlight the possible reason for little in vivo activity seen for current front-line anti-NRP drugs, and we introduce a new methodology for future drug screening as well as a potential role for dapsone inclusion within the current treatment regime.

Superior efficacy of combination antibiotic therapy versus monotherapy in a mouse model of Lyme disease

“…Dapsone in dual or triple combinations with rifampicin, clofazimine, or rifampicin + clofazimine were also effective at eradicating viable Bb. The combinations of dapsone with rifampicin, clofazimine or both are already the therapies of choice to treat multidrug-resistant M. tuberculosis or leprosy (dapsone) and have ample evidence for safety and tolerability in that population (Pattyn, 1990;Seydel et al, 1994;Barr, 2010;Gibson et al, 2022). Furthermore, clinical studies have demonstrated efficacy of dapsone combination therapy in Lyme disease patients with chronic symptoms/PTLD (Horowitz and Freeman, 2019;Horowitz and Freeman, 2020;FIGURE 2 Representative images taken of xenodiagnostic tick midgut smears stained for Borrelia.…”

Insight into novel anti-mucormycosis therapies: investigation of new anti-mucormycosis laser-induced photodynamic therapy based on a sulphone bis-compound loaded silica nanoemulsion

“…Moreover, dapsone, chemically known as 4,4′-diaminodiphenylsulfone, is an old commercially-available widely-used broad-spectrum synthetic sulfone-based antibiotic. 11–19 Dapsone exhibits potent antimicrobial, 20 anti-inflammatory, 21 and antiprotozoal efficacy and is widely employed for the treatment of different skin disorders, such as leprosy and acne, 22 as well as the skin issues that arise in gonorrhea. 18 In addition, dapsone is mainly utilized in the preparation of topical treatments for dermatitis herpetiformis and acne vulgaris.…”