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Table 2 Considerations and challenges to overcome in developing drugs to treat non-tuberculous mycobacterial pulmonary disease

From: Meeting the challenges of NTM-PD from the perspective of the organism and the disease process: innovations in drug development and delivery

Challenge

Detailed overview

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

  1. MIC, minimum inhibitory concentration; NTM, non-tuberculous mycobacteria; NTM-PD, non-tuberculous mycobacterial pulmonary disease. Adapted from [52]