Antibiotic-resistant pathogens are a global health threat. Small molecules that inhibit bacterial virulence have been suggested as alternatives or adjuncts to conventional antibiotics, they may limit pathogenesis and increase susceptibility host killing. Staphylococcus aureus is major cause of invasive skin soft tissue infections (SSTIs) in both the hospital community settings, it also becoming increasingly antibiotic resistant. Quorum sensing (QS) mediated by accessory gene regulator (agr)...

The lack of effective and well-tolerated therapies against antibiotic-resistant bacteria is a global public health problem leading to prolonged treatment increased mortality. To improve the efficacy existing antibiotic compounds, we introduce new method for strategically inducing hypersensitivity in pathogenic bacteria. Following systematic verification that AcrAB-TolC efflux system one major determinants intrinsic resistance levels Escherichia coli, have developed short antisense oligomer...

Pseudomonas aeruginosa is a highly virulent, multidrug-resistant pathogen that causes significant morbidity and mortality in hospitalized patients particularly devastating with cystic fibrosis. Increasing antibiotic resistance coupled decreasing numbers of antibiotics the developmental pipeline demands novel antibacterial approaches. Here, we tested peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), which inhibit translation complementary mRNA from specific, essential genes...

Abstract Treatment of prosthetic joint infection (PJI) usually requires surgical replacement the infected and weeks antibiotic therapy, due to formation biofilm. We introduce a non-invasive method for thermal destruction biofilm on metallic implants using high-frequency (>100 kHz) alternating magnetic fields (AMF). In vitro investigations demonstrate >5-log reduction in bacterial counts after 5 minutes AMF exposure. Confocal scanning electron microscopy confirm removal matrix...

During a screen of the Nebraska Transposon Mutant Library, we identified 71 mutations in Staphylococcus aureus genome that altered hemolysis on blood agar medium. Although many these disrupted genes known to affect production alpha-hemolysin, two them were associated with an apparent operon, designated vfrAB, had not been characterized previously. Interestingly, ΔvfrB mutant exhibited only minor effects transcription hla gene, encoding when grown broth, as well RNAIII, posttranscriptional...

Staphylococcus aureus contains an autoinducing quorum-sensing system encoded within the agr operon that coordinates expression of virulence genes required for invasive infection. Allelic variation has generated four specific groups, I–IV, each which secretes a distinct peptide pheromone (AIP1-4) drives signaling. Because signaling mediates phenotypic change in this pathogen from adherent colonizing phenotype to one associated with considerable tissue injury and invasiveness, we postulated...

In late 2015, the first example of a transferrable polymyxin resistance mechanism in Gram-negative pathogens, MCR-1, was reported. Since that report, MCR-1 has been described to occur many and MCR-1-mediated rapidly determined: an ethanolamine is attached lipid A phosphate groups, rendering membrane more electropositive repelling positively charged polymyxins. Acquisition clinically significant because polymyxins are frequently last-line antibiotics used treat extensively resistant...

Numerous Gram-negative bacteria are becoming increasingly resistant to multiple, if not all, classes of existing antibiotics. Multidrug-resistant Pseudomonas aeruginosa a major cause health care-associated infections in variety clinical settings, endangering patients who immunocompromised or those suffer from chronic infections, such as people with cystic fibrosis (CF).

Objectives: The objective of this study was to test the efficacy an inhibitor New Delhi metallo-β- lactamase (NDM-1). Inhibiting expression type antibiotic-resistance gene has potential restore antibiotic susceptibility in all bacteria carrying gene. Methods: We have constructed a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) that selectively inhibits NDM-1 and examined its ability meropenem vitro vivo. Results:In vitro, PPMO reduced MIC for three different genera...

Klebsiella pneumoniae is an opportunistic pathogen and many strains are multidrug resistant. KPC one of the most problematic resistance mechanisms, as it confers to β-lactams, including carbapenems. A promising platform technology for treating infections caused by MDR pathogens nucleic acid-like synthetic oligomers that silence bacterial gene expression antisense mechanism.To test a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) in mouse model K. infection.PPMOs were...

Sex bias in innate defense against Staphylococcus aureus skin and soft tissue infection (SSTI) is dependent on both estrogen production by the host S. secretion of virulence factor, α-hemolysin (Hla). The impact signaling immune system most often studied terms nuclear receptors ERα ERβ. However, potential contribution G protein-coupled receptor (GPER) to infectious disease, particularly with respect infection, has not been addressed. Using a murine model SSTI, we found that GPER activation...

Staphylococcus aureus is an opportunistic, pathogenic bacteria that causes significant morbidity and mortality. As antibiotic resistance by S. continues to be a serious concern, developing novel drug therapies combat these infections vital. Quorum sensing inhibitors (QSI) dampen virulence facilitate clearance the host immune system blocking quorum signaling promotes upregulation of genes controlled accessory gene regulator (agr) operon. While QSIs have shown therapeutic promise in mouse...

A major hurdle in vaccine development is the difficulty identifying relevant target epitopes and then presenting them to immune system a context that mimics their native conformation. We have engineered novel virus-like-particle (VLP) technology able display complex libraries of random peptide sequences on surface-exposed loop coat protein without disruption folding or VLP assembly. This allows us use same particle for both affinity selection immunization, integrating power epitope discovery...

One proposed solution to the crisis of antimicrobial resistant (AMR) infections is development molecules that potentiate activity antibiotics for AMR bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). Rather than develop broad spectrum compounds, we developed a peptide could narrow antibiotic, oxacillin. In this way, combination treatment narrowly target pathogen and limit impact on host flora. We peptide, ASU014, composed S. binding inhibitory conjugated branched...

The Burkholderia cepacia complex is a group of Gram-negative bacteria that are opportunistic pathogens in immunocompromised individuals, such as those with cystic fibrosis (CF) or chronic granulomatous disease (CGD). intrinsically resistant to many antibiotics and the lack antibiotic development necessitates novel therapeutics. Peptide-conjugated phosphorodiamidate morpholino oligomers antisense molecules inhibit bacterial mRNA translation. Targeting PPMOs gene acpP, which essential for...

Staphylococcus aureus fatty acid kinase FakA is necessary for the incorporation of exogenous acids into lipid membrane. We previously demonstrated that inactivation fakA leads to decreased α-hemolysin (Hla) production but increased expression proteases SspAB and aureolysin in vitro, ΔfakA mutant causes larger lesions than wild type (WT) during murine skin infection. As expected, necrosis Hla dependent presence or absence FakA, as both hla mutants are unable cause skin. At day 4...

Lysozyme (lytic enzyme) as first reported and described by Fleming¹in 1922 is a substance found in various body tissues secretions which has the property of dissolving certain bacteria. Since Fleming's initial work, lysozyme been studied many different investigators. Wolff²has on its chemistry, Hoder³on relation to immunology, Anderson⁴on importance vitamin A deficiency, Corper⁵on tuberculosis, Meyer, Thompson, Palmer...

Abstract The G protein‐coupled estrogen receptor, also known as GPER1 or originally GPR30, is found in various tissues, indicating its diverse functions. It typically present immune cells, suggesting role regulating responses to infectious diseases. Our previous studies have shown that G‐1, a selective GPER agonist, can limit the pathogenesis mediated by Staphylococcus aureus alpha‐hemolysin (Hla). aids clearing bacteria mouse skin infection model and restricts surface display of Hla ADAM10...

Staphylococcus aureus is the leading cause of skin and soft tissue infections (SSTIs) mounting antibiotic resistance requires innovative treatment strategies. S. uses secreted cyclic autoinducing peptides (AIPs) accessory gene regulator (agr) operon to coordinate expression virulence factors required for invasive infection. Of four agr alleles (agr types I-IV corresponding AIPs1-4), type I isolates are most frequently associated with Cyclization via a thiolactone bond essential AIP function;...

We previously reported sex differences in innate susceptibility to Staphylococcus aureus skin infection and that bone marrow neutrophils (BMN) from female mice have an enhanced ability kill S. ex vivo compared with those of male mice. However, the mechanism(s) driving this bias neutrophil killing not been reported. Given role opsonins such as complement, well their receptors, recognition clearance, we investigated contribution bactericidal capacity BMN. found levels C3 serum CR3 (CD11b/CD18)...

Since the introduction by Duggar of chlortetracycline (Aureomycin) in 1948 and subsequent search for discovery other antibiotics, an enormous amount work has been done clinicians bacteriologists on antibiotic specificity. Selection a suitable treating infections ears sinuses during World War II was simple. Near front lines only sulfonamides were available use. The widely used locally systemically, with good results. In nine years following war, approximately 45,000 veterans seen at ENT...

The pore-forming cytotoxin α-hemolysin, or Hla, is a critical Staphylococcus aureus virulence factor that promotes infection by causing tissue damage, excessive inflammation, and lysis of both innate adaptive immune cells, among other cellular targets. In this study, we asked whether virus-like particle (VLP)-based vaccine targeting Hla could attenuate S. Hla-mediated pathogenesis. VLPs are versatile platforms can be used to display target antigens in multivalent array, typically resulting...