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Host-directed therapies are emerging as a promising tool in the curing of difficult-to-treat infections, such as those caused by drug-resistant bacteria. In this study, we aim to test the potential activity of the FDA- and EMA-approved drugs cysteamine and cystamine against <i>Mycobacterium abscessus</i>. In human macrophages (differentiated THP-1 cells), these drugs restricted <i>M. abscessus</i> growth similar to that achieved by amikacin. Here, we use the human ex vivo granuloma-like structures (GLS) model of infection with the <i>M. abscessus</i> rough (MAB-R) and smooth (MAB-S) variants to study the activity of new therapies against <i>M. abscessus</i>. We demonstrate that cysteamine and cystamine show a decrease in the number of total GLSs per well in the MAB-S and MAB-R infected human peripheral blood mononuclear cells (PBMCs). Furthermore, combined administration of cysteamine or cystamine with amikacin resulted in enhanced activity against the two <i>M. abscessus</i> morpho variants compared to treatment with amikacin only. Treatment with cysteamine and cystamine was more effective in reducing GLS size and bacterial load during MAB-S infection compared with MAB-R infection. Moreover, treatment with these two drugs drastically quenched the exuberant proinflammatory response triggered by the MAB-R variant. These findings showing the activity of cysteamine and cystamine against the R and S <i>M. abscessus</i> morphotypes support the use of these drugs as novel host-directed therapies against <i>M. abscessus</i> infections.