Graduate Thesis Or Dissertation
 

Quantitative Analysis of Mycobacterium avium subsp. hominissuis and Mycobacterium abscessus subs. abscessus Proteome in Response to Antibiotics and During Exposure to Different Environmental Conditions

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  • M. avium subsp. hominissuis (MAH) and M. abscessus subsp. abscessus (MAB) both belong to the clinically important non-tuberculous mycobacterial (NTM) group that infect immunocompromised patients with AIDS and individuals with underlining lung conditions such as bronchiectasis or cystic fibrosis. The main challenge of treating MAH and MAB patients is an inability to rapidly kill pathogens with multiple compounds even at the bactericidal concentrations. As a result, MAV requires prolonged treatment for 15 to 18 months and MAB is the multidrug resistant pathogenic NTM that requires treatment for 18-24 month. The need for prolonged therapy for MAH and MAB treatment influences the development of persistent and drug-resistant infections. The reason why several drugs at their bactericidal concentrations take several months to eliminate MAH and MAB infections is unknown. The main goal of our research was to investigate MAH and MAB proteome response under aerobic, anaerobic and biofilm conditions that are encountered in patient lungs and intracellularly with or without bactericidal concentrations of antibiotics. In order to identify proteome remodeling and metabolic changes enhancing bacterial tolerance during biofilm and anaerobic conditions with or without exposure of bactericidal concentrations of antibiotics, we performed the relative protein quantitative analysis using Tandem Mass Tag Mass Spectrometry sequencing. We identified proteome remodeling of MAH under aerobic, anaerobic and biofilm conditions in presence or absence of amikacin (4 μg/ml) and clarithromycin (16 μg/ml), and the response was compared. Overall, 4,000 MAH proteins were identified across all experimental group. In both anaerobic and biofilm conditions, MAH upregulates pantothenate and CoA biosynthesis, glycerolipid metabolism, nitrogen metabolism and chloroalkene degradation which are known to be associated with bacterial tolerance in M. tuberculosis. In anaerobic and biofilm conditions following drug treatments peptidoglycan biosynthesis, glycerophospholipid metabolism, and protein export pathways were highly upregulated. We also identified proteome remodeling of MAB under aerobic anaerobic and biofilm conditions in presence or absence of amikacin (32μg/ml) and linezolid (128 μg/ml), and the response was compared. We found glycolysis/gluconeogenesis, citrate cycle (TCA cycle), oxidative phosphorylation, nitrogen metabolism, and glyoxylate and dicarboxylate metabolism pathways expressed exclusively in both anaerobic and biofilm conditions. Following 24h drug treatments in anaerobic and biofilm conditions, the glycerophospholipid metabolism and oxidative phosphorylation are commonly observed. Cumulatively, our work significantly advances the knowledge on MAH and MAB tolerance mechanism in biofilms and anaerobic conditions, and how they tolerate high concentrations of antibiotics. Current multidrug regimens fail to effectively eliminate MAH and MAB infection and eradicates MAH in only 40% to 60% of individuals, and success rate for MAB treatment is only 25% to 42%. Our study has identified several novel targets that may contribute to the rapid killing of MAH and MAB.
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