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Species-Wide Phylogenomics of the Staphylococcus aureus Agr Operon Revealed Convergent Evolution of Frameshift Mutations.

ABSTRACT: Staphylococcus aureus is a prominent nosocomial pathogen that causes several life-threatening diseases, such as pneumonia and bacteremia. S. aureus modulates the expression of its arsenal of virulence factors through sensing and integrating responses to environmental signals. The agr (accessory gene regulator) quorum sensing (QS) system is a major regulator of virulence phenotypes in S. aureus. There are four agr specificity groups each with a different autoinducer peptide sequence encoded by the agrD gene. Although agr is critical for the expression of many toxins, paradoxically, S. aureus strains often have nonfunctional agr activity due to loss-of-function mutations in the four-gene agr operon. To understand patterns in agr variability across S. aureus, we undertook a species-wide genomic investigation. We developed a software tool (AgrVATE; https://github.com/VishnuRaghuram94/AgrVATE) for typing and detecting frameshift mutations in the agr operon. In an analysis of over 40,000 S. aureus genomes, we showed a close association between agr type and S. aureus clonal complex. We also found a strong linkage between agrBDC alleles (encoding the peptidase, autoinducing peptide itself, and peptide sensor, respectively) but not agrA (encoding the response regulator). More than 5% of the genomes were found to have frameshift mutations in the agr operon. While 52% of these frameshifts occurred only once in the entire species, we observed cases where the recurring mutations evolved convergently across different clonal lineages with no evidence of long-term phylogenetic transmission, suggesting that strains with agr frameshifts were evolutionarily short-lived. Overall, genomic analysis of agr operon suggests evolution through multiple processes with functional consequences that are not fully understood. IMPORTANCE Staphylococcus aureus is a globally pervasive pathogen that produces a plethora of toxic molecules that can harm host immune cells. Production of these toxins is mainly controlled by an active agr quorum-sensing system, which senses and responds to bacterial cell density. However, there are many reports of S. aureus strains with genetic changes leading to impaired agr activity that are often found during chronic bloodstream infections and may be associated with increased disease severity. We developed an open-source software called AgrVATE to type agr systems and identify mutations. We used AgrVATE for a species-wide genomic survey of S. aureus, finding that more than 5% of strains in the public database had nonfunctional agr systems. We also provided new insights into the evolution of these genetic mutations in the agr system. Overall, this study contributes to our understanding of a common but relatively understudied means of virulence regulation in S. aureus.

SUBMITTER: Raghuram V

PROVIDER: S-EPMC8768832 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mutations in the beta-subunit of bacterial RNA polymerase (RpoB) cause resistance to rifampin (Rifr), a critical antibiotic for treatment of multidrug-resistant Staphylococcus aureus. In vitro studies have shown that RpoB mutations confer decreased susceptibility to other antibiotics, but the clinical relevance is unknown. Here, by analyzing 7,099 S. aureus genomes, we demonstrate that the most prevalent RpoB mutations promote clinically relevant phenotypic plasticity resulting in the emergence of stable S. aureus lineages, associated with increased risk of therapeutic failure through generation of small-colony variants (SCVs) and coresistance to last-line antimicrobial agents. We found eight RpoB mutations that accounted for 93% (469/505) of the total number of Rifr mutations. The most frequently selected amino acid substitutions affecting residue 481 (H481N/Y) were associated with worldwide expansions of Rifr clones spanning decades. Recreating the H481N/Y mutations confirmed no impact on S. aureus growth, but the H481N mutation promoted the emergence of a subpopulation of stable Rifr SCVs with reduced susceptibility to vancomycin and daptomycin. Recreating the other frequent RpoB mutations showed similar impacts on resistance to these last-line agents. We found that 86% of all Rifr isolates in our global sample carried the mutations promoting cross-resistance to vancomycin and 52% to both vancomycin and daptomycin. As four of the most frequent RpoB mutations confer only low-level Rifr, equal to or below some international breakpoints, we recommend decreasing these breakpoints and reconsidering the appropriate use of rifampin to reduce the fixation and spread of these clinically deleterious mutations. IMPORTANCE Increasing antibiotic resistance in the major human pathogen Staphylococcus aureus is threatening the ability to treat patients with these infections. Recent laboratory studies suggest that mutations in the gene commonly associated with rifampin resistance may also impact susceptibility to other last-line antibiotics in S. aureus; however, the overall frequency and clinical impact of these mutations are unknown. By mining a global collection of clinical S. aureus genomes and by mutagenesis experiments, this work reveals that common rifampin-induced rpoB mutations promote phenotypic plasticity that has led to the global emergence of stable, multidrug-resistant S. aureus lineages that are associated with increased risk of therapeutic failure through coresistance to other last-line antimicrobials. We recommend decreasing susceptibility breakpoints for rifampin to allow phenotypic detection of critical rpoB mutations conferring low resistance to rifampin and reconsidering the appropriate use of rifampin to reduce the fixation and spread of these deleterious mutations globally.

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Species-Wide Phylogenomics of the Staphylococcus aureus Agr Operon Revealed Convergent Evolution of Frameshift Mutations.

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