Publication Date

4-16-2020

Document Type

Thesis

Degree Name

Master of Science in Biology (MS)

Committee Chair

Mott, Daniel J.

Abstract

Mycobacterium abscessus is non-tuberculosis, rapid-growing mycobacterium (RGM), initially described in 1953. It is considered to be an important human pathogen that is found in hospital settings. This organism is responsible for soft tissue infections, disseminated infections in immunocompromised patients, after lung transplants, as well as common in bronchopulmonary infections in patients with cystic fibrosis. It accounts for up to 80% of lung diseases caused by RGM. Mycobacterium abscessus possesses resistance to a wide variety of antibiotics, thus, no standardized treatment for this pathogen has been established. While currently available antimicrobials are useful against most infections caused by this pathogen, lung infections have proven to be particularly troublesome. Following the American Thoracic Society (ATS) recommendations for the treatment of M. abscessus infections, treatment response rates were below 60% for maintenance of negative sputum cultures for more than 12 months, with frequent adverse effects reported. While rifamycins have potent activity against M. tuberculosis, they have no activity against M. abscessus. It is known that M. abscessus possesses two resistance mechanisms to deactivate rifamycins. Genomic analyses show that the DNA sequence of the ropB gene of M. abscessus (type strain ATCC 19977) is identical to rifampicin-susceptible strains of M. tuberculosis. M. abscessus harbors an ADP-ribosyl transferase gene (GenBank ID MAB_0591) and data indicates that the arr homolog of M. abscessus confers high-level resistance to rifamycin. A series of three rifamycin derivatives (coded ARR-1-21, KC-1-51, and S1-35) with potential anti-bacterial activity against M. abscessus were synthetized. Minimal inhibitory concentration (MIC) assays were performed against clinical strains of M. abscessus to evaluate the antimicrobial activity of the made compounds. For further testing and better understanding of the permeability of the molecules a series of disc diffusion tests were performed against two clinical strains of M. abscessus. The results indicate that the innate resistance to rifampicin can be overcome, and while the three molecules show considerable antimicrobial activity against M. abscessus in both tests performed, KC-1-51 was the derivative that showed the most promising results.

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