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Structure of the 70S Ribosome from the Human Pathogen Acinetobacter baumannii in Complex with Clinically Relevant Antibiotics.

ABSTRACT: Acinetobacter baumannii is a Gram-negative bacterium primarily associated with hospital-acquired, often multidrug-resistant (MDR) infections. The ribosome-targeting antibiotics amikacin and tigecycline are among the limited arsenal of drugs available for treatment of such infections. We present high-resolution structures of the 70S ribosome from A. baumannii in complex with these antibiotics, as determined by cryoelectron microscopy. Comparison with the ribosomes of other bacteria reveals several unique structural features at functionally important sites, including around the exit of the polypeptide tunnel and the periphery of the subunit interface. The structures also reveal the mode and site of interaction of these drugs with the ribosome. This work paves the way for the design of new inhibitors of translation to address infections caused by MDR A. baumannii.

SUBMITTER: Nicholson D

PROVIDER: S-EPMC7546915 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Biological processes that govern bacterial proliferation and survival in the host-environment(s) are likely to be vastly different from those that are required for viability in nutrient-rich laboratory media. Consequently, growth-based antimicrobial screens performed in conditions modeling aspects of bacterial disease states have the potential to identify new classes of antimicrobials that would be missed by screens performed in conventional laboratory media. Accordingly, we performed screens of the Selleck library of 853 FDA approved drugs for agents that exhibit antimicrobial activity toward the Gram-negative bacterial pathogen Acinetobacter baumannii during growth in human serum, lung surfactant, and/or the organism in the biofilm state and compared those results to that of conventional laboratory medium. Results revealed that a total of 90 compounds representing 73 antibiotics and 17 agents that were developed for alternative therapeutic indications displayed antimicrobial properties toward the test strain in at least one screening condition. Of the active library antibiotics only four agents, rifampin, rifaximin, ciprofloxacin and tetracycline, exhibited antimicrobial activity toward the organism during all screening conditions, whereas the remainder were inactive in ≥ 1 condition; 56 antibiotics were inactive during serum growth, 25 and 38 were inactive toward lung surfactant grown and biofilm-associated cells, respectively, suggesting that subsets of antibiotics may outperform others in differing infection settings. Moreover, 9 antibiotics that are predominantly used for the treatment Gram-positive pathogens and 10 non-antibiotics lacked detectable antimicrobial activity toward A. baumannii grown in conventional medium but were active during ≥ 1 alternative growth condition(s). Such agents may represent promising anti-Acinetobacter agents that would have likely been overlooked by antimicrobial whole cell screening assays performed in traditional laboratory screening media.

Dataset Information

Structure of the 70S Ribosome from the Human Pathogen Acinetobacter baumannii in Complex with Clinically Relevant Antibiotics.

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