Abstract
Global control of tuberculosis has become increasingly complicated with the emergence of multidrug-resistant strains of Mycobacterium tuberculosis First-line treatments are anchored by two antibiotics, rifampin and isoniazid. Most rifampin resistance occurs through the acquisition of missense mutations in the rifampin resistance-determining region, an 81-base pair region encoding the rifampin binding site on the β subunit of RNA polymerase (rpoB). Although these mutations confer a survival advantage in the presence of rifampin, they may alter the normal process of transcription, thereby imposing significant fitness costs. Because the downstream biochemical consequences of the rpoB mutations are unknown, we used an organism-wide screen to identify the number and types of lipids changed after rpoB mutation. A new mass spectrometry-based profiling platform systematically compared ∼10,000 cell wall lipids in a panel of rifampin-resistant mutants within two genetically distinct strains, CDC1551and W-Beijing. This unbiased lipidomic survey detected quantitative alterations (>2-fold, p < 0.05) in more than 100 lipids in each mutant. By focusing on molecular events that change among most mutants and in both genetic backgrounds, we found that rifampin resistance mutations lead to altered concentrations of mycobactin siderophores and acylated sulfoglycolipids. These findings validate a new organism-wide lipidomic analysis platform for drug-resistant mycobacteria and provide direct evidence for characteristic remodeling of cell wall lipids in rifampin-resistant strains of M. tuberculosis The specific links between rifampin resistance and named lipid factors provide diagnostic and therapeutic targets that may be exploited to address the problem of drug resistance.
Highlights
Mycobacterium tuberculosis remains a leading cause of death worldwide from an infectious disease [1]
We focused on three mutations, H526Y, S531L, and Q513E, because we had identified them in both genetic backgrounds and because they correspond to the characteristic mutations occurring among clinical isolates during natural tuberculosis epidemics [28, 29]
Most lipidomic or metabolomic methods focus on phospholipids, which constitute the bilayers of model eukaryotic cells and most bacteria, mycobacteria produce fewer phospholipids and more types of neutral lipids, including more than 90 subclasses of lipids that are unique to the order Actinomycetales [20, 23]
Summary
Mycobacterium tuberculosis remains a leading cause of death worldwide from an infectious disease [1]. Strains resistant to rifampin alone, once considered rare, make up a large percentage of monoresistant M. tuberculosis isolates [3, 4] Resistance to both rifampin and isoniazid constitutes a clinical state of multidrug resistance, which necessitates treatment with a complicated second-line regimen that is both more toxic and less effective than standard chemotherapy [5]. Cell surface polyketides, interface directly with the host and regulate immunogens that are exposed to the host [14] and have been known to control the permeability of the organism [15,16,17,18] in ways that might affect the transport of other drugs If these candidate cell wall changes can be reproducibly associated with drug resistance phenotypes, altered lipids might function as biochemical markers of the drug-resistant state [19]
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