title: Lack of antimicrobial bactericidal activity in Mycobacterium abscessus.
abstract: Antibiotic therapy of infections caused by the emerging pathogen Mycobacterium abscessus is challenging due to the organism's natural resistance toward most clinically available antimicrobials. We investigated the bactericidal activity of antibiotics commonly administered in M. abscessus infections in order to better understand the poor therapeutic outcome. Time-kill curves were generated for clinical M. abscessus isolates, Mycobacterium smegmatis, and Escherichia coli by using antibiotics commonly categorized as bactericidal (amikacin and moxifloxacin) or bacteriostatic (tigecycline and linezolid). In addition, the impact of aminoglycoside-modifying enzymes on the mode of action of substrate and nonsubstrate aminoglycosides was studied by using M. smegmatis as a model organism. While amikacin and moxifloxacin were bactericidal against E. coli, none of the tested compounds showed bactericidal activity against M. abscessus. Further mechanistic investigations of the mode of action of aminoglycosides in M. smegmatis revealed that the bactericidal activity of tobramycin and gentamicin was restored by disruption of the chromosomal aac(2') gene in the mycobacterial genome. The lack of bactericidal antibiotics in currently recommended treatment regimens provides a reasonable explanation for the poor therapeutic outcome in M. abscessus infection. Our findings suggest that chromosomally encoded drug-modifying enzymes play an important role in the lack of aminoglycoside bactericidal activity against rapidly growing mycobacteria.
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland Nationales Zentrum für Mykobakterien, Universität Zürich, Zürich, Switzerland.
authors.forename: Florian P
authors.initials: FP
authors.lastname: Maurer
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: Vera L
authors.initials: VL
authors.lastname: Bruderer
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland Nationales Zentrum für Mykobakterien, Universität Zürich, Zürich, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ritter
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Castelberg
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: Guido V
authors.initials: GV
authors.lastname: Bloemberg
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland Nationales Zentrum für Mykobakterien, Universität Zürich, Zürich, Switzerland boettger@imm.uzh.ch.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Böttger
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000254:growth & development; D009170:Nontuberculous Mycobacteria / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D000123:Acetyltransferases; C443113:aminoglycoside 2'-N-acetyltransferase
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