title: A multidrug-resistant, acr1-deficient clinical isolate of Mycobacterium tuberculosis is unimpaired for replication in macrophages.
abstract: Multidrug-resistant tuberculosis (MDR-TB) poses a serious threat to global public health. The mutations responsible for drug resistance in Mycobacterium tuberculosis have been identified, but what impact these mutations have on bacterial fitness is controversial. We analyzed 3 MDR strains of M. tuberculosis obtained from human immunodeficiency virus-negative patients with chronic pulmonary TB. One of these strains harbored a chromosomal deletion encompassing 15 open reading frames. Genes deleted in this strain included acr1, which encodes the virulence factor alpha-crystallin (Acr) 1, a protein that has been reported to be essential for M. tuberculosis replication in macrophages. We found that all 3 MDR isolates, including the acr1-deficient strain, replicated in cultured murine and human macrophages with the same kinetics as H37Rv, a virulent laboratory strain. These observations challenge the prevailing view that MDR bacteria are less fit than drug-susceptible bacteria and indicate that Acr1 is dispensable for bacterial growth in the human lung.
authors.affiliation: Laboratory of Infection Biology, The Rockefeller University, New York, New York 10021, USA. timmj@rockefeller.edu
authors.forename: Juliano
authors.initials: J
authors.lastname: Timm
authors.forename: Natalia
authors.initials: N
authors.lastname: Kurepina
authors.forename: Barry N
authors.initials: BN
authors.lastname: Kreiswirth
authors.forename: Frank A
authors.initials: FA
authors.lastname: Post
authors.forename: Gabrielle B
authors.initials: GB
authors.lastname: Walther
authors.forename: Helen C
authors.initials: HC
authors.lastname: Wainwright
authors.forename: Linda-Gail
authors.initials: LG
authors.lastname: Bekker
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
authors.forename: John D
authors.initials: JD
authors.lastname: McKinney
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002876:Chromosomes, Bacterial / Q000235:genetics; D015169:Colony Count, Microbial; D024901:Drug Resistance, Multiple, Bacterial; D015658:HIV Infections / Q000150:complications; D006651:Histocytochemistry; D006801:Humans; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development* / Q000302:isolation & purification / Q000472:pathogenicity; D017384:Sequence Deletion; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology; D037521:Virulence Factors / Q000235:genetics* / Q000502:physiology; D038201:alpha-Crystallins / Q000235:genetics* / Q000502:physiology
chemical_list: D037521:Virulence Factors; D038201:alpha-Crystallins