Peroxynitrite Induces Antibiotic Tolerance in Staphylococcus aureus

2020 ◽  
Vol 159 ◽  
pp. S38-S39
Author(s):  
Jenna Beam ◽  
John Shook ◽  
Nikki Wagner ◽  
Edward Moreira Bahnson ◽  
Sarah Rowe ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Tolerance

scholarly journals Author Correction: Reactive oxygen species induce antibiotic tolerance during systemic Staphylococcus aureus infection

2020 ◽  
Vol 5 (3) ◽  
pp. 526-526 ◽  
Author(s):  
Sarah E. Rowe ◽  
Nikki J. Wagner ◽  
Lupeng Li ◽  
Jenna E. Beam ◽  
Alec D. Wilkinson ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Staphylococcus Aureus ◽  
Reactive Oxygen ◽  
Antibiotic Tolerance ◽  
Oxygen Species ◽  
Aureus Infection

scholarly journals Gel-Entrapped Staphylococcus aureus Bacteria as Models of Biofilm Infection Exhibit Growth in Dense Aggregates, Oxygen Limitation, Antibiotic Tolerance, and Heterogeneous Gene Expression

2016 ◽  
Vol 60 (10) ◽  
pp. 6294-6301 ◽  
Author(s):  
Breana Pabst ◽  
Betsey Pitts ◽  
Ellen Lauchnor ◽  
Philip S. Stewart
Keyword(s):  
Staphylococcus Aureus ◽  
Fluorescent Protein ◽  
Specific Growth ◽  
Matrix Material ◽  
Antibiotic Tolerance ◽  
Glass Capillary ◽  
Host Matrix ◽  
Content Type ◽  
Biofilm Infection

ABSTRACTAn experimental model that mimicked the structure and characteristics ofin vivobiofilm infections, such as those occurring in the lung or in dermal wounds where no biomaterial surface is present, was developed. In these infections, microbial biofilm forms as cell aggregates interspersed in a layer of mucus or host matrix material. This structure was modeled by filling glass capillary tubes with an agarose gel that had been seeded withStaphylococcus aureusbacteria and then incubating the gel biofilm in medium for up to 30 h. Confocal microscopy showed that the bacteria formed in discrete pockets distributed throughout the gel matrix. These aggregates enlarged over time and also developed a size gradient, with the clusters being larger near the nutrient- and oxygen-supplied interface and smaller at greater depths. Bacteria entrapped in gels for 24 h grew slowly (specific growth rate, 0.06 h−1) and were much less susceptible to oxacillin, minocycline, or ciprofloxacin than planktonic cells. Microelectrode measurements showed that the oxygen concentration decreased with depth into the gel biofilm, falling to values less than 3% of air saturation at depths of 500 μm. An anaerobiosis-responsive green fluorescent protein reporter gene for lactate dehydrogenase was induced in the region of the gel where the measured oxygen concentrations were low, confirming biologically relevant hypoxia. These results show that the gel biofilm model captures key features of biofilm infection in mucus or compromised tissue: formation of dense, distinct aggregates, reduced specific growth rates, local hypoxia, and antibiotic tolerance.

scholarly journals Interruption of the tricarboxylic acid cycle in Staphylococcus aureus leads to increased tolerance to innate immunity

2021 ◽  
Vol 7 (4) ◽  
pp. 513-527
Author(s):  
Alexis M. Hobbs ◽  
◽  
Kennedy E. Kluthe ◽  
Kimberly A. Carlson ◽  
Austin S. Nuxoll
Keyword(s):  
Staphylococcus Aureus ◽  
Immune System ◽  
Innate Immune System ◽  
Tricarboxylic Acid Cycle ◽  
Fold Increase ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Innate Immune ◽  
Antibiotic Tolerance ◽  
Males And Females

<abstract> <p><italic>Staphylococcus aureus</italic> is widely known for its resistance and virulence causing public health concerns. However, antibiotic tolerance is also a contributor to chronic and relapsing infections. Previously, it has been demonstrated that persister formation is dependent on reduced tricarboxylic acid (TCA) cycle activity. Persisters have been extensively examined in terms of antibiotic tolerance but tolerance to antimicrobial peptides (AMPs) remains largely unexplored. AMPs are a key component of both the human and <italic>Drosophila</italic> innate immune response. TCA cycle mutants were tested to determine both antibiotic and AMP tolerance. Challenging with multiple classes of antibiotics led to increased persister formation (100- to 1,000-fold). Similarly, TCA mutants exhibited AMP tolerance with a 100- to 1,000-fold increase in persister formation when challenged with LL-37 or human β-defensin 3 (hβD3). The ability of TCA cycle mutants to tolerate the innate immune system was further examined with a <italic>D. melanogaster</italic> model. Both males and females infected with TCA cycle mutants exhibited increased mortality and had higher bacterial burdens (1.5 log) during the course of the infection. These results suggest increasing the percentage of persister cells leads to increased tolerance to components of the innate immune system.</p> </abstract>

scholarly journals The Toxin Antitoxin MazEF DrivesStaphylococcus aureusChronic Infection

2019 ◽  
Author(s):  
Dongzhu Ma ◽  
Jonathan B. Mandell ◽  
Niles P. Donegan ◽  
Ambrose L. Cheung ◽  
Wanyan Ma ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Biofilm Formation ◽  
Chronic Infection ◽  
Critical Role ◽  
Antimicrobial Treatment ◽  
Antibiotic Tolerance ◽  
Chronic Infections ◽  
Biofilm Growth ◽  
Increased Risk

AbstractStaphylococcus aureusis the major organism responsible for surgical implant infections. Antimicrobial treatment of these infections often fails leading to expensive surgical intervention and increased risk of mortality to the patient. The challenge in treating these infections is associated with the high tolerance ofS. aureusbiofilm to antibiotics. MazEF, a toxin-antitoxin system, is thought to be an important regulator of this phenotype, but its physiological function inS. aureusis controversial. Here, we examined the role of MazEF in developing chronic infections by comparing growth and antibiotic tolerance phenotypes in threeS. aureusstrains to their corresponding strains with disruption ofmazFexpression. Strains lackingmazFproduction showed increased biofilm growth, and decreased biofilm antibiotic tolerance. Deletion oficaADBCin themazF::tn background suppressed the growth phenotype observed withmazF-disrupted strains, suggesting the phenotype wasica-dependent. We confirmed these phenotypes in our murine animal model. Loss ofmazFresulted in increased bacterial burden and decreased survival rate compared to its wild-type strain demonstrating that loss of themazFgene caused an increase inS. aureusvirulence. Although lack ofmazFgene expression increasedS. aureusvirulence, it was more susceptible to antibioticsin vivo. Combined, the ability ofmazFto inhibit biofilm formation and promote biofilm antibiotic tolerance plays a critical role in transitioning from an acute to chronic infection that is difficult to eradicate with antibiotics alone.ImportanceSurgical infections are one of the most common types of infections obtained in a hospital.Staphylococcus aureusis the most common pathogen associated with this infection. These infections are resilient and difficult to eradicate as the bacteria form a biofilm, a community of bacteria held together by an extracellular matrix. Compared to bacteria floating in liquid, bacteria in a biofilm are more resistant to antibiotics. The mechanism behind how bacteria develop this resistance and establish a chronic infection is unknown. We demonstrate thatmazEF, a toxin-antitoxin gene, inhibits biofilm formation and promotes biofilm antibiotic tolerance which allowsS. aureusto transition from an acute to chronic infection that cannot be eradicated with antibiotics but is less virulent. This gene not only makes the bacteria more tolerant to antibiotics but makes the bacteria more tolerant to the host.

scholarly journals The msaABCR Operon Regulates Persister Formation by Modulating Energy Metabolism in Staphylococcus aureus

2021 ◽  
Vol 12 ◽  
Author(s):  
Shanti Pandey ◽  
Gyan S. Sahukhal ◽  
Mohamed O. Elasri
Keyword(s):  
Staphylococcus Aureus ◽  
Energy Metabolism ◽  
Tca Cycle ◽  
Antibiotic Tolerance ◽  
Atp Content ◽  
Persister Cells ◽  
Metabolic Genes ◽  
Starting Point ◽  
Metabolic Activities ◽  
Systemic Infections

Staphylococcus aureus is a major human pathogen that causes chronic, systemic infections, and the recalcitrance of these infections is mainly due to the presence of persister cells, which are a bacterial subpopulation that exhibits extreme, yet transient, antibiotic tolerance accompanied by a transient halt in growth. However, upon cessation of antibiotic treatment, a resumption in growth of persister cells causes recurrence of infections and treatment failure. Previously, we reported the involvement of msaABCR in several important staphylococcal phenotypes, including the formation of persister cells. Additionally, observations of the regulation of several metabolic genes by the msaABCR operon in transcriptomics and proteomics analyses have suggested its role in the metabolic activities of S. aureus. Given the importance of metabolism in persister formation as our starting point, in this study we demonstrated how the msaABCR operon regulates energy metabolism and subsequent antibiotic tolerance. We showed that deletion of the msaABCR operon results in increased tricarboxylic acid (TCA) cycle activity, accompanied by increased cellular ATP content and higher NADH content in S. aureus cells. We also showed that msaABCR (through MsaB) represses the ccpE and ndh2 genes, thereby regulating TCA cycle activity and the generation of membrane potential, respectively. Together, the observations from this study led to the conclusion that msaABCR operon deletion induces a metabolically hyperactive state, leading to decreased persister formation in S. aureus.

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