Challenge | Detailed overview |
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NTM organism—hydrophobicity and innate resistance | • Permeability barrier because of hydrophobic, lipid-rich double membrane cell envelope • Prevention of antibiotic binding due to non-polar cell surface • Ability to switch morphology reversibly, which can vary drug susceptibility • Potential to express efflux pumps to prevent intracellular drug accumulation and enzymes to limit drug activity • Natural and acquired drug resistance through target gene polymorphisms to prevent drug binding and modification of target binding site upon drug exposure |
Acquired drug resistance | • Genomic mutations (mutations in the target or other related genes to confer high-level resistance after long-course treatment) • Lateral gene transfer of drug resistance genes (less frequent but possible) |
Correlation between in vitro MIC and clinical outcomes | • In vitro conditions to determine mycobacterial growth do not mimic the lung environment • Growth in airway mucous and biofilms |
Intracellular growth and sequestration into phagocytic cells | • Intracellular growth, survival, and persistence (macrophages, monocytes) • Ability to escape from normal macrophage apoptosis mechanisms • Ability to limit normal acidification of phagolysosomes • Ability to decrease normal apoptosis mechanisms and block autophagy |
Mucous and biofilm growth | • Ability to form and reside within biofilms • Capability of long-term viability due to ability to adopt a non-replicating dormant state under nutrient or oxygen starvation • High mucous production in NTM-PD assists in bacterial evasion from antimicrobial therapy and reduced antimicrobial susceptibility |