Ancestral antibiotic resistance in Mycobacterium tuberculosis

Abstract

Chemotherapeutic options to treat tuberculosis are severely restricted by the intrinsic resistance of Mycobacterium tuberculosis to the majority of clinically applied antibiotics. Such resistance is partially provided by the low permeability of their unique cell envelope. Here we describe a complementary system that coordinates resistance to drugs that have penetrated the envelope, allowing mycobacteria to tolerate diverse classes of antibiotics that inhibit cytoplasmic targets. This system depends on whiB7, a gene that pathogenic Mycobacterium shares with Streptomyces, a phylogenetically related genus known as the source of diverse antibiotics. In M. tuberculosis, whiB7 is induced by subinhibitory concentrations of antibiotics (erythromycin, tetracycline, and streptomycin) and whiB7 null mutants (Streptomyces and Mycobacterium) are hypersusceptible to antibiotics in vitro. M. tuberculosis is also antibiotic sensitive within a monocyte model system. In addition to antibiotics, whiB7 is induced by exposure to fatty acids that pathogenic Mycobacterium species may accumulate internally or encounter within eukaryotic hosts during infection.Gene expression profiling analyses demonstrate that whiB7 transcription determines drug resistance by activating expression of a regulon including genes involved in ribosomal protection and antibiotic efflux. Components of the whiB7 system may serve as attractive targets for the identification of inhibitors that render M. tuberculosis or multidrug-resistant derivatives more antibioticsensitive.multidrug resistance ͉ Streptomyces ͉ WhiB ͉ microarray ͉ gene expression

Expression, production and release of the Eis protein by Mycobacterium tuberculosis during infection of macrophages and its effect on cytokine secretion

“…They concluded that eis may contribute to the enhanced growth of the 210 strain in human macrophages. Morris et al (2005) have also recently demonstrated that eis is a component of the whiB7 regulon, whose expression is upregulated by exposure to sublethal concentrations of antibiotics or fatty acids such as would be encountered within the host macrophage during infection. These reports in conjunction with the data presented here point to a significant but not yet clearly defined role for eis in the pathogenesis of M. tuberculosis.…”

Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis

“…Despite intensive focus on the primary drug-target interaction and its maladaptive consequences, knowledge of the endogenous mechanisms used by bacteria to resist antibiotic activity is incomplete and centred chiefly around mechanisms associated with the drug-target interaction, such as drug efflux pumps and antibiotic-and/or target-modifying enzymes 3 . However, growing evidence has implicated a broader range of physiologic factors [7][8][9][10]27 .…”

“…Recent work has expanded the scope of physiologic factors associated with antibiotic resistance to include broader bacterial stress responses, such as the SOS DNA stress response, heatshock response and oxidative stress response, as well as changes in metabolic state and activity [7][8][9][10][11][12] . These antibiotic-induced responses then contribute functionally to resistance.…”

BCG Vaccines: Their mechanisms of attenuation and impact on safety and protective efficacy

“…30,31,47,48 A molecular phylogeny based on these hypersensitive to several antibiotics. 78 Transcriptional analysis of all whiB genes in M. tb showed differential expression patterns in response to different stress conditions. 79 For example, WhiB3 was shown to interact with SigA 77 and responds to oxygen and nitric oxide, and is important for regulation of carbon metabolism.…”