title: Pyrazinamide resistance in Mycobacterium tuberculosis fails to bite?
abstract: In contrast to most other antimycobacterial drugs where--particularly in multidrug-resistant (MDR) strains--a limited number of resistance mutations dominate, pyrazinamide (PZA) resistance associated mutations remain highly diverse with limited clustering. This apparent lack of evolutionary selection for successful PZA resistance mechanisms deserves attention. A clear understanding of the epidemiology of PZA resistance acquisition and spread would be expected to result in important insights into how PZA might be better exploited in treatment regimens to minimize the amplification of Mycobacterium tuberculosis (MTB) drug resistance. We propose that PZA resistance typically induces a fitness cost that impairs MTB transmission. This would explain the lack of extensive clustering for PZA-resistant mutants. Our hypothesis also leads to a series of testable predictions which we outline that could confirm or refute our ideas.
authors.affiliation: KIT Biomedical Research, Royal Tropical Institute (KIT), Amsterdam, the Netherlands.
authors.forename: Alice L
authors.initials: AL
authors.lastname: den Hertog
authors.affiliation: KIT Biomedical Research, Royal Tropical Institute (KIT), Amsterdam, the Netherlands.
authors.forename: Sarah
authors.initials: S
authors.lastname: Sengstake
authors.affiliation: KIT Biomedical Research, Royal Tropical Institute (KIT), Amsterdam, the Netherlands r.anthony@kit.nl.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Anthony
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D018562:Disease Transmission, Infectious; D024881:Drug Resistance, Bacterial; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000502:physiology; D011718:Pyrazinamide / Q000494:pharmacology*; D014376:Tuberculosis / Q000382:microbiology / Q000635:transmission; D014774:Virulence
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide
keywords: Mycobacterium tuberculosis; multidrug resistance; pyrazinamide; resistance; transmission, fitness