Mycobacterium abscessus is an emerging threat, causing infections that are difficult to treat due to intrinsic resistance to most antibiotics. Determinants of M. abscessus physiology and pathogenesis remain poorly understood, hampering therapeutic development. Here, we show that in M. abscessus, the lprg-mfs operon is essential for virulence in macrophages and in mice. Loss of lprg-mfs in M. abscessus causes accumulation of the glycolipid lipoarabinomannan (LAM) on the cell surface and in culture supernatant suggesting that this system participates in LAM import. This contrasts with its proposed role in M. tuberculosis where lprg-mfs has been implicated in the export of various lipids. Consistent with altered lipid distribution, the lprg-mfs mutant displays severe defects in mycomembrane permeability, fluidity, and integrity, and expression of mfs alone restores only a subset of these phenotypes, revealing a surprising uncoupling of envelope fluidity and permeability. Using a suppressor screen to further investigate factors that control the distribution of lipoarabinomannan we find that a point mutation in the unannotated gene MAB₀995 can fully or partially complement all deletion mutant phenotypes. Our data also show that lipoarabinomannan in the mycomembrane is dynamically regulated in response to environmental conditions, including hypoxia and macrophage infection. Together, these findings redefine the role of LprG/Mfs in mycobacterial cell envelope homeostasis and reveal unexpected plasticity in mycomembrane lipid regulation in M. abscessus.
Campbell-Kruger et al. (Thu,) studied this question.