Biomedical subjects

Robert J Ulrich

Publications and source records attributed to Robert J Ulrich.

3 recordsLinked to original sources

PubMed2026

Hospital transmission of methicillin-resistant Staphylococcus aureus driven by addictive mupA plasmids.

BACKGROUND: Resistance to mupirocin, a cornerstone of Staphylococcus aureus decolonization, is a recognized cause of decolonization failure. Its role in hospital transmission is unknown. METHODS: We conducted genomic surveillance of >10,000 S. aureus isolates from adult patients at two urban hospitals where mupirocin decolonization is routine. Bacterial phenotypes and fitness were evaluated in vitro and in murine colonization models to interpret surveillance results. RESULTS: Genome sequencing identified 475 hospital transmission events; conventional surveillance detected none. The plasmid-mediated resistance determinant mupA ( ileS2 ) was enriched eightfold in methicillin-resistant S. aureus (MRSA) relative to methicillin-susceptible strains. mupA was associated with nearly threefold greater hospital transmission, especially within healthcare-associated MRSA lineages. Surprisingly, multiple independently evolved inactivating mutations in the essential chromosomal gene ileS1 co-occurred with mupA , creating plasmid addiction in which mupA became indispensable for bacterial survival. Plasmid carriage activated the stringent response and reduced colonization fitness, but also conferred collateral tolerance to disinfectants such as ethanol and peroxide. Although addiction further reduced S. aureus fitness, it increased plasmid transfer, promoting spread despite these costs. Unexpectedly, we found a mupirocin-dependent vulnerability to isoleucine limitation, revealing a potential strategy to target mupA -mediated resistance. CONCLUSIONS: Hospital transmission of mupirocin-resistant MRSA is promoted by plasmids that create an evolutionary trap in which mupirocin use selects for bacterial dependence on costly resistance elements. These findings suggest that reducing mupirocin use alone is unlikely to eliminate resistance, underscore the need for genomic surveillance and resistance testing, and provide a framework for strategies to preserve mupirocin effectiveness. MAJOR POINT: This work shows that mupirocin resistance promotes hospital transmission of MRSA, identifies a previously unappreciated mechanism of plasmid addiction, and exposes a collateral vulnerability. These findings underscore the need for genomic surveillance and provide a framework to preserve mupirocin effectiveness.

Journal Article↗

PubMed2024

Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress.

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic state in response to diminished metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived 'memory' of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Cybb-/-) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.

Staphylococcus aureus↗

PubMed2024

Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress.

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr increased both respiration and fermentation but decreased ATP levels and growth, suggesting that Δagr cells assume a hyperactive metabolic state in response to reduced metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived "memory" of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Nox2-/-) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.

Staphylococcus aureus↗