Abstract
Tuberculosis, caused by Mycobacterium tuberculosis, is an urgent global health problem requiring new drugs, new drug targets and an increased understanding of antibiotic resistance. We have determined the mode of resistance to a series of arylamide compounds in M. tuberculosis We isolated M. tuberculosis resistant mutants to two arylamide compounds which are inhibitory to growth under host-relevant conditions (butyrate as a sole carbon source). Thirteen mutants were characterized, and all had mutations in Rv2571c; mutations included a premature stop codon and frameshifts as well as non-synonymous polymorphisms. We isolated a further ten strains with mutations in Rv2571c with resistance. Complementation with a wild-type copy of Rv2571c restored arylamide sensitivity. Over-expression of Rv2571c was toxic in both wild-type and mutant backgrounds. We constructed M. tuberculosis strains with an unmarked deletion of the entire Rv2571c gene by homologous recombination and confirmed that these were resistant to the arylamide series. Rv2571c is a member of the aromatic amino acid transport family and has a fusaric acid resistance domain which is associated with compound transport. Since loss or inactivation of Rv2571c leads to resistance, we propose that Rv2571c is involved in the import of arylamide compounds.
Highlights
Tuberculosis, caused by Mycobacterium tuberculosis, is an urgent global health problem requiring new drugs, new drug targets, and an increased understanding of antibiotic resistance
There is an urgent need for new drug targets as well as an increased understanding of antibiotic resistance in the causative pathogen Mycobacterium tuberculosis [2, 3]
These compounds are of interest because they are only active against M. tuberculosis using butyrate as the sole carbon source; in the presence of glucose as the sole carbon source, compounds lose activity
Summary
Tuberculosis, caused by Mycobacterium tuberculosis, is an urgent global health problem requiring new drugs, new drug targets, and an increased understanding of antibiotic resistance. We have determined the mode of resistance to be a series of arylamide compounds in M. tuberculosis. We isolated M. tuberculosis resistant mutants to two arylamide compounds which are inhibitory to growth under host-relevant conditions (butyrate as a sole carbon source). There is an urgent need for new drug targets as well as an increased understanding of antibiotic resistance in the causative pathogen Mycobacterium tuberculosis [2, 3]. Since M. tuberculosis utilizes fatty acids as a carbon source in vivo, we previously developed a whole-cell screen with butyrate as the sole carbon source [5]. Using this high-throughput screen, we identified a series of aryl amides with good activity against M. tuberculosis. We demonstrate that resistance is due to a loss of activity of the putative transport system Rv2571c
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