Elucidation of a novel mechanism of macrolide resistance in Mycobacterium abscessus

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Project Summary: Mycobacterium abscessus (Mab) is a rapidly growing NTM causing skin and soft tissue infections and pulmonary infections in patients with chronic lung damage, such as prior tuberculosis and cystic fibrosis. Mab stands apart as one of the most antibiotic resistant microbial species, making its infections incredibly difficult to treat. Although macrolides are a cornerstone of therapy against NTMs, they are ineffective against Mab. Intrinsic resistance to macrolides is attributed to macrolide inducible expression of methylases that modify the 23S rRNA comprising the macrolide binding site. To date this is the only known mechanism of macrolide resistance in Mab. We have identified an additional determinant, MAB_3042c, that confers inducible macrolide resistance in Mab. MAB_3042c is homologous to the universally conserved HflX proteins which have been shown to function as ribosome splitting factors. HflX proteins have not been previously implicated in antibiotic resistance suggesting that Mab_3402 could be a novel type of HflX. However, Mab_3402 also shows similarity to ribosome protection factors, which are characterized by an extended loop that inserts into the nascent polypeptide exit tunnel (NPET) and occludes the binding pocket of macrolides. In this project we will explore the function of Mab_3042 in macrolide resistance in Mab. In Aim 1, we will determine the function of MAB_3042c in ribosome splitting and ribosome protection as well as determine the role of these functions in macrolide resistance. In Aim 2 we will study the spectrum of antibiotics that are affected by MAB_3042c. The findings will provide a platform for a long-term structure- function study to gain mechanistic insight into Mab_3402c dependent macrolide resistance in Mab.