Although almost all mycobacterial species are saprophytic environmental organisms, a few, such as Mycobacterium tuberculosis, have evolved to cause transmissible human infection. By analyzing the recent emergence and spread of the environmental organism M. abscessus through the global cystic fibrosis population, we have defined key, generalizable steps involved in the pathogenic evolution of mycobacteria. We show that epigenetic modifiers, acquired through horizontal gene transfer, cause saltational increases in the pathogenic potential of specific environmental clones. Allopatric parallel evolution during chronic lung infection then promotes rapid increases in virulence through mutations in a discrete gene network; these mutations enhance growth within macrophages but impair fomite survival. As a consequence, we observe constrained pathogenic evolution while person-to-person transmission remains indirect, but postulate accelerated pathogenic adaptation once direct transmission is possible, as observed for M. tuberculosis. Our findings indicate how key interventions, such as early treatment and cross-infection control, might restrict the spread of existing mycobacterial pathogens and prevent new, emergent ones.

Bacterial porins permit permeation of hydrophilic nutrients and antibiotics across the outer membrane but also contribute to proton leak from the periplasmic space, suggesting that their activity might be dynamically regulated. Here we show, in Escherichia coli, that porin permeability is controlled by changes in periplasmic ions, inhibited by periplasmic acidification, thereby limiting proton loss during electron transport chain activity, and enhanced during starvation, promoting nutrient uptake. Growth in glucose increases periplasmic potassium through activating the voltage-gated channel Kch, triggering enhanced porin permeation and membrane action potentials. This metabolic control of porin permeability explains the recognized decrease in antibiotic susceptibility when bacteria are grown in lipid media and the impact of mutations in central metabolism genes on drug resistance, identifying Kch as a therapeutic target to improve bacterial killing by antibiotics.