Ribosome protection by ABC‐F proteins—Molecular mechanism and potential drug design

Abstract

Members of the ATP-binding cassette F (ABC-F) proteins confer resistance to several classes of clinically important antibiotics through ribosome protection. Recent structures of two ABC-F proteins, Pseudomonas aeruginosa MsrE and Bacillus subtilis VmlR bound to ribosome have shed light onto the ribosome protection mechanism whereby drug resistance is mediated by the antibiotic resistance domain (ARD) connecting the two ATP binding domains. ARD of the E site bound MsrE and VmlR extends toward the drug binding region within the peptidyl transferase center (PTC) and leads to conformational changes in the P site tRNA acceptor stem, the PTC, and the drug binding site causing the release of corresponding drugs. The structural similarities and differences of the MsrE and VmlR structures likely highlight an universal ribosome protection mechanism employed by antibiotic resistance (ARE) ABC-F proteins. The variable ARD domains enable this family of proteins to adapt the protection mechanism for several classes of ribosome-targeting drugs. ARE ABC-F genes have been found in numerous pathogen genomes and multi-drug resistance conferring plasmids. Collectively they mediate resistance to a broader range of antimicrobial agents than any other group of resistance proteins and play a major role in clinically significant drug resistance in pathogenic bacteria. Here, we review the recent structural and biochemical findings on these emerging resistance proteins, offering an update of the molecular basis and implications for overcoming ABC-F conferred drug resistance.

Does Shiga Toxin-Producing Escherichia coli and Listeria monocytogenes Contribute Significantly to the Burden of Antimicrobial Resistance in Uruguay?

“…The lin gene was detected in all the analyzed strains and encoded for a lincomycin resistance ABC-F type ribosomal protection protein, a member of the ATP-binding cassette F (ABC-F) proteins ( 38 ). We did not find descriptions of this mechanism in L. monocytogenes , but we did find the lin gene in almost all genomes of this species in NCBI Pathogen Detection Isolates Browser ( https://www.ncbi.nlm.nih.gov/pathogens/ ) suggesting that this mechanism could be involved in the natural resistance to lincomycin.…”

Characterization of Two Macrolide Resistance-Related Genes in Multidrug-Resistant Pseudomonas aeruginosa Isolates

“…In this work, using large-scale sequencing of pooled genomic DNA of 262 strains, only two macrolide-related resistance genes, mphE and msrE , were identified in seven and four P. aeruginosa strains, respectively. This finding indicated that the known macrolide resistance genes are not prevalent in clinical P. aeruginosa isolates, although this was not the first time these two genes have been detected in P. aeruginosa ( Ding et al 2018 ; Ero et al 2019 ).…”

“…The mphE gene encodes a macrolide-2’-phospho-transferase, an intracellular enzyme with the ability to transfer the γ-phosphate of one nucleotide triphosphate to the 2’-OH group of macrolide compounds, thereby destroying the critical interaction between macrolides and A2058 ( Fyfe et al 2016 ). The msrE gene belongs to the ABC-F subfamily of ATP-binding cassette protein, which mediates a recently described new mechanism of resistance to macrolides ( Janvier et al 2017 ; Ero et al 2019 ).…”

Structural basis of resistance to lincosamide, streptogramin A, and pleuromutilin antibiotics by ABCF ATPases in Gram-positive pathogens

“…One group of bacterial ABCFs, which are termed antibiotic resistance (ARE) ABCFs (Dorrian & Kerr, 2009), confer resistance to antibiotics that bind to the 50S subunit of the bacterial ribosome (Ero et al , 2019; Ousalem et al ., 2019; Sharkey & O’Neill, 2018; Wilson et al ., 2020). Characterized ARE ABCFs are found predominantly in Gram-positive bacteria, including human and animal pathogens, typically have a restricted host specificity, and can be further divided into eight subfamilies (Allignet et al , 1992; Murina et al ., 2019; Wilson et al ., 2020).…”