Journal Article

Quorum Sensing, Virulence, and Antibiotic Resistance of USA100 Methicillin-Resistant Staphylococcus aureus Isolates

Crosby, Heidi A., Heilmann, Kristopher, Kavanaugh, Jeffrey S., Horswill, Alexander R., Parlet, Corey P., Cho, Young-Saeng, Diekema, Daniel J., Grundstad, Morgan L., Kwiecinski, Jakub M.

2019

Overview

USA100 health care-associated MRSA isolates are highly antibiotic resistant and can cause invasive disease across all patient populations. Even though USA100 strains are some of the most frequently identified causes of infections, little is known about virulence regulation in these isolates. Our study demonstrates that the USA100 agr quorum-sensing system is important for the control of toxin and exoenzyme production and that the agr system has a key role in skin infection. In some USA100 isolates, the agr system is important for growth in the presence of low levels of antibiotics. Altogether, our findings demonstrate that the USA100 agr system is a critical regulator of virulence and that it may make a contribution to the optimal survival of these MRSA strains in the presence of antibiotics. Methicillin-resistant Staphylococcus aureus (MRSA) infections impact all patient populations both in the community and in health care settings. Despite advances in our knowledge of MRSA virulence, little is known about the regulatory mechanisms of USA100 health care-associated MRSA isolates, which are the second most frequently identified MRSA isolates found in all infections. This work focused on the contribution of the USA100 agr type II quorum-sensing system to virulence and antibiotic resistance. From a MRSA strain collection, we selected 16 representative USA100 isolates, constructed mutants with Δ agr mutations, and characterized selected strain pairs for virulence factor expression, murine skin infection, and antibiotic resistance. For each strain pair, hemolysis and extracellular protease expression were significantly greater in the wild-type (WT) strains than in the Δ agr mutants. Similarly, mice challenged with the WT strains had larger areas of dermonecrosis and greater weight loss than those challenged with the Δ agr mutants, demonstrating that the USA100 agr system regulates virulence. Although USA100 isolates exhibit a high level of antibiotic resistance, the WT and Δ agr strain pairs showed no difference in MICs by MIC testing. However, in the presence of a sub-MIC of vancomycin, most of the USA100 Δ agr mutants exhibited slower growth than the WT isolates, and a couple of the Δ agr mutants also grew more slowly in the presence of a sub-MIC of cefoxitin. Altogether, our findings demonstrate that the USA100 agr system is a critical regulator of virulence, and it may have a contribution to the optimal survival of these MRSA strains in the presence of antibiotics. IMPORTANCE USA100 health care-associated MRSA isolates are highly antibiotic resistant and can cause invasive disease across all patient populations. Even though USA100 strains are some of the most frequently identified causes of infections, little is known about virulence regulation in these isolates. Our study demonstrates that the USA100 agr quorum-sensing system is important for the control of toxin and exoenzyme production and that the agr system has a key role in skin infection. In some USA100 isolates, the agr system is important for growth in the presence of low levels of antibiotics. Altogether, our findings demonstrate that the USA100 agr system is a critical regulator of virulence and that it may make a contribution to the optimal survival of these MRSA strains in the presence of antibiotics.

• Publisher: American Society for Microbiology
• Subject: agr / Animals / Anti-Bacterial Agents - pharmacology / Antibiotic resistance / Antibiotics / Bacterial Proteins - genetics / Blood / Cefoxitin / Disease / Drug resistance / Drug Resistance, Multiple, Bacterial / Global health / Host-Microbe Biology / Humans / Immunology / Kinases / Medicine / Methicillin / Methicillin-Resistant Staphylococcus aureus - drug effects / Methicillin-Resistant Staphylococcus aureus - genetics / Methicillin-Resistant Staphylococcus aureus - pathogenicity / Mice / Mice, Inbred BALB C / Microbial Sensitivity Tests / Minimum inhibitory concentration / MRSA / Peptides / Quorum Sensing / Skin / Staphylococcal Infections - microbiology / Staphylococcus aureus / Staphylococcus infections / Statistical analysis / Survival / Trans-Activators - genetics / USA100 / Vancomycin / Virulence / Virulence factors / Virulence Factors - genetics