Abstract
Nontuberculous mycobacteria (NTM) have recently emerged as important pathogens among cystic fibrosis (CF) patients worldwide. Mycobacterium abscessus is becoming the most worrisome NTM in this cohort of patients and recent findings clarified why this pathogen is so prone to this disease. M. abscessus drug therapy takes up to 2 years and its failure causes an accelerated lung function decline. The M. abscessus colonization of lung alveoli begins with smooth strains producing glycopeptidolipids and biofilm, whilst in the invasive infection, “rough” mutants are responsible for the production of trehalose dimycolate, and consequently, cording formation. Human-to-human M. abscessus transmission was demonstrated among geographically separated CF patients by whole-genome sequencing of clinical isolates worldwide. Using a M. abscessus infected CF zebrafish model, it was demonstrated that CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction seems to have a specific role in the immune control of M. abscessus infections only. This pathogen is also intrinsically resistant to many drugs, thanks to its physiology and to the acquisition of new mechanisms of drug resistance. Few new compounds or drug formulations active against M. abscessus are present in preclinical and clinical development, but recently alternative strategies have been investigated, such as phage therapy and the use of β-lactamase inhibitors.
Highlights
Cystic fibrosis (CF) is an autosomal recessive disease characterized by the involvement of respiratory, gastrointestinal, and male reproductive tracts, even if most of the morbidity and mortality arises from CF lung disease [1,2]
Clinical isolate sequencing has demonstrated that human-to-human Mycobacterium abscessus subsp. abscessus (Mab) transmission is possible, further threatening CF patient health and contributing to its spread [14,43,44]
Mab virulence among CF patients is related to three important factors: (1) the transition from the S variant, important for colonization, to the R strain, fundamental for cell invasion [53]; (2) the GLPs of S strains, which are able to masque trehalose dimycolate (TDM) and other lipids responsible for the activation of the innate immune system [51]; (3) the role of CFTR mutations in promoting Mab infections, as CFTR seems to have a specific role in the immune control of only this pathogen [69]
Summary
Cystic fibrosis (CF) is an autosomal recessive disease characterized by the involvement of respiratory, gastrointestinal, and male reproductive tracts, even if most of the morbidity and mortality arises from CF lung disease [1,2]. The Mab R strains induce more aggressive and invasive pulmonary disease, in CF patients; these mutants are more frequently isolated after a long persistent infection and are associated with increased lung function decline [48,53,61,62,63,64]. Clofazimine and bedaquiline are two drugs used for TB treatment; recently, clofazimine was introduced in Mab therapy, whilst bedaquiline is under preclinical evaluation Both drugs have a common mechanism of resistance in both M. tuberculosis and Mab [84,90], consisting of mutations in the gene coding for the repressor of the efflux pump MmpS5-MmpL5 (Rv0678 in M. tuberculosis and MAB_2299c in Mab) [84,90]. The strong induction of WhiB7 confers amikacin and clarithromycin resistance; deletion of MAB_3508c gene renders Mab more susceptible to amikacin and clarithromycin [8,79]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
