title: Intrinsic rifamycin resistance of Mycobacterium abscessus is mediated by ADP-ribosyltransferase MAB_0591.
abstract: Rifampicin, a potent first-line TB drug of the rifamycin group, shows only little activity against the emerging pathogen Mycobacterium abscessus. Reportedly, bacterial resistance to rifampicin is associated with polymorphisms in the target gene rpoB or the presence of enzymes that modify and thereby inactivate rifampicin. The aim of this study was to investigate the role of the MAB_0591 (arrMab)-encoded rifampicin ADP-ribosyltransferase (Arr_Mab) in innate high-level rifampicin resistance in M. abscessus.
  
  
  
  Recombinant Escherichia coli and Mycobacterium tuberculosis strains expressing MAB_0591 were generated, as was an M. abscessus deletion mutant deficient for MAB_0591. MIC assays were used to study susceptibility to rifampicin and C25 carbamate-modified rifamycin derivatives.
  
  
  
  Heterologous expression of MAB_0591 conferred rifampicin resistance to E. coli and M. tuberculosis Rifamycin MIC values were consistently lower for the M. abscessus ΔarrMabmutant as compared with the M. abscessus ATCC 19977 parental type strain. The rifamycin WT phenotype was restored after complementation of the M. abscessus ΔarrMabmutant with arrMabFurther MIC data demonstrated that a C25 modification increases rifamycin activity in WT M. abscessus However, MIC studies in the M. abscessus ΔarrMabmutant suggest that C25 modified rifamycins are still subject to modification by Arr_Mab CONCLUSIONS: Our findings identify Arr_Mab as the major innate rifamycin resistance determinant of M. abscessus. Our data also indicate that Arr_Mab-mediated rifamycin resistance in M. abscessus can only in part be overcome by C25 carbamate modification.
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, Zürich 8006, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rominski
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, Zürich 8006, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Roditscheff
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, Zürich 8006, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Selchow
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, Zürich 8006, Switzerland.|Nationales Zentrum für Mykobakterien, Gloriastrasse 30/32, Zürich 8006, Switzerland.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Böttger
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, Zürich 8006, Switzerland psander@imm.uzh.ch.|Nationales Zentrum für Mykobakterien, Gloriastrasse 30/32, Zürich 8006, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Sander
mesh_terms: D036002:ADP Ribose Transferases / Q000378:metabolism*; D000995:Antitubercular Agents / Q000494:pharmacology*; D003001:Cloning, Molecular; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D017353:Gene Deletion; D008826:Microbial Sensitivity Tests; D009161:Mycobacterium / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012294:Rifamycins / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D011994:Recombinant Proteins; D012294:Rifamycins; D036002:ADP Ribose Transferases