Abstract
Mycobacterium abscessus is an opportunistic pathogen whose treatment is confounded by widespread multidrug resistance. The therapeutic use of bacteriophages against Mycobacterium abscessus infections offers a potential alternative approach, although the spectrum of phage susceptibilities among M. abscessus isolates is not known. We determined the phage infection profiles of 82 M. abscessus recent clinical isolates and find that colony morphotype-rough or smooth-is a key indicator of phage susceptibility. None of the smooth strains are efficiently killed by any phages, whereas 80% of rough strains are infected and efficiently killed by at least one phage. The repertoire of phages available for potential therapy of rough morphotype infections includes those with relatively broad host ranges, host range mutants of Mycobacterium smegmatis phages, and lytically propagated viruses derived from integrated prophages. The rough colony morphotype results from indels in the glycopeptidolipid synthesis genes mps1 and mps2, negating reversion to smooth as a common route to phage resistance. Resistance is thus rare, and although mutations in polyketide synthesis, uvrD2, and rpoZ can confer resistance, these likely also impair survival in vivo The expanded therapeutic repertoire and the resistance profiles show that small cocktails or single phages could be suitable for controlling infections with rough strains.IMPORTANCEMycobacterium abscessus infections in cystic fibrosis patients are challenging to treat due to widespread antibiotic resistance. The therapeutic use of lytic bacteriophages presents a new potential strategy, but the great variation among clinical M. abscessus isolates demands determination of phage susceptibility prior to therapy. Elucidation of the variation in phage infection and factors determining it, expansion of the suite of therapeutic phage candidates, and a greater understanding of phage resistance mechanisms substantially advances the potential for broad implementation of new therapeutic options for M. abscessus infections.
Highlights
Mycobacterium abscessus is an opportunistic pathogen whose treatment is confounded by widespread multidrug resistance
Following the successful treatment of a disseminated M. abscessus infection with a bacteriophage cocktail [17], we received 82 M. abscessus strains from 78 different patients for characterization of phage susceptibilities; 54 (69%) of these are from within the United States and the others are from 10 different other countries (Table 1)
The observation that smooth strains with abundant surface GPLs are not efficiently killed by phages is in contrast to the finding that GPLs are required for M. smegmatis infection by phage I3 [39]
Summary
Mycobacterium abscessus is an opportunistic pathogen whose treatment is confounded by widespread multidrug resistance. The rough colony morphotype results from indels in the glycopeptidolipid synthesis genes mps and mps, negating reversion to smooth as a common route to phage resistance. IMPORTANCE Mycobacterium abscessus infections in cystic fibrosis patients are challenging to treat due to widespread antibiotic resistance. The therapeutic use of lytic bacteriophages presents a new potential strategy, but the great variation among clinical M. abscessus isolates demands determination of phage susceptibility prior to therapy. Nontuberculous mycobacteria (NTM) are frequent pathogens of cystic fibrosis (CF) and bronchiectasis patients [1, 2] They are commonly refractory to treatment due to widespread antibiotic resistance and antibiotic toxicity over the required long treatment regimens [2,3,4]. Smooth-to-rough transitions are often nonreversible, temperature-dependent variation has been reported for one variant [11, 15, 16]
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