Targeting Mycolic Acid Transport by Indole-2-carboxamides for the Treatment of Mycobacterium abscessus Infections

Mycobacterium abscessus is a fast-growing,
multidrug-resistant organism that has emerged as a clinically significant
pathogen in cystic fibrosis (CF) patients. The intrinsic resistance
of M. abscessus to most commonly available
antibiotics seriously restricts chemotherapeutic options. Herein,
we report the potent activity of a series of indolecarboxamides against M. abscessus. The lead compounds, 6 and 12, exhibited strong activity in vitro against a wide panel
of M. abscessus isolates and in infected
macrophages. High resistance levels to the indolecarboxamides appear
to be associated with an A309P mutation in the mycolic acid transporter
MmpL3. Biochemical analyses demonstrated that while de novo mycolic
acid synthesis remained unaffected, the indolecarboxamides strongly
inhibited the transport of trehalose monomycolate, resulting in the
loss of trehalose dimycolate production and abrogating mycolylation
of arabinogalactan. Our data introduce a hereto unexploited chemical
structure class active against M. abscessus infections with promising translational development possibilities
for the treatment of CF patients.