The emerging pathogen Mycobacterium abscessus (Mab) is the most pathogenic and resistant to chemotherapy of all of the rapid-growing mycobacterium (RGM). Mab has been found in hospital water supplies, traumatic skin infections, post-surgical soft tissue infections, is a leading pathogen in lung transplant infections and is a common pathogen in cystic fibrosis patients. Clinical studies on therapeutic outcome are rare and cure rates do not exceed 30-50% with the currently available antimicrobials. A standardized treatment regimen has not been established, partially due to the high levels of natural antibiotic resistance and the lack of bactericidal activity of commonly administered compounds. Rifamycins are potent anti-Mycobacterium tuberculosis agents but have no activity against Mab. Mycobacterium have two resistance mechanisms to deactivate rifamycins. Genomic analyses shows that the DNA sequence of the rpoB gene of Mab (type strain ATCC 19977) is identical to rifampicin-susceptible strains of M. tuberculosis. Mab harbors an ADP-ribosyltransferase gene (GenBank ID MAB_0591) and preliminary data indicate that the Arr homolog of Mab confers high-level resistance to rifampicin. We have prepared a series of rifamycin derivatives that have potent anti-bacterial activity against Mab. We believe our improved anti-bacterial activity is due to insensitivity to Arr enzymatic deactivation. We have identified two series that show very potent antimicrobial activity and we will describe the structure activity relationships of these new series.

New compounds for the treatment of Mycobacterium abscessus infections

253rd National Meeting (2017)

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