Bacteriology Commons^™

Synergistic Cefiderocol-Containing Antibiotic Combinations Active Against Highly Drug-Resistant Acinetobacter Baumannii Patient Isolates With Diverse Resistance Mechanisms, Justin Halim, Andrew P. Keane, Jeannete Bouzo, Tope Aderibigbe, Jessica A. Chicola, Katie T. Nolan, Keertana Jonnalagadda, Jason X. Tran, Valerie J. Carabetta

Rowan-Virtua School of Osteopathic Medicine Departmental Research

BACKGROUND: Acinetobacter baumannii is a nosocomial pathogen known for rapidly developing resistance to nearly all antibiotics, including last-line agents. Cefiderocol, a novel siderophore cephalosporin, has shown in vitro activity against A. baumannii and is now used clinically, but resistance is emerging. Data on cefiderocol-based antibiotic combinations are limited.

OBJECTIVES: To evaluate the in vitro activity of cefiderocol alone and in combination with other antibiotics against XDR and PDR A. baumannii clinical isolates, and to explore resistance mechanisms underlying cefiderocol synergy.

METHODS: We tested 21 XDR/PDR clinical isolates and one NDM-1-producing strain using broth microdilution and checkerboard assays with cefiderocol and …

Exploring The Role Of Lysine Acetylation During Biofilm Formation In Bacillus Subtilis, Jennifer Nguyen, Briana Ericka Reid, Valerie Carabetta

Rowan-Virtua Research Day

Biofilms are structured communities of bacterial cells encased in a self-produced extracellular matrix, composed of polysaccharides, extracellular DNA, and proteins. Bacteria in a biofilm pose significant challenges in healthcare due to their resistance to disinfectants and tolerance to antibiotics. In some species, histone-like proteins were found to be important structural components of the biofilm. Nε-Lysine acetylation is a widespread post-translational modification (PTM) in bacteria, which can alter a protein’s function. The histone-like protein HBsu in Bacillus subtilis is acetylated at seven sites in vivo. We hypothesized that the acetylation state of HBsu may alter biofilm structure or the genetic programming, …

The Effects Of Specialized Pro-Resolving Mediator Lipoxin A4 On Pseudomonas Aeruginosa Biofilms And Interactions With Monocytes, Julianne M. Thornton

Graduate School of Biomedical Sciences Theses and Dissertations

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen known as a major cause of hospital-acquired secondary infections, commonly causing chronic respiratory infections in immunocompromised individuals, especially those with cystic fibrosis, and often found in wound infections. P. aeruginosa uses the quorum sensing pathway to readily form protective biofilms, which reduce the efficacy of antibiotics and access by host immune cells to eradicate the pathogen. Specialized pro-resolving mediators (SPMs) are lipids endogenously produced by the host immune response to infection to aid in infection resolution. One SPM, Lipoxin A4 (LxA4), has been shown to be a robust quorum sensing inhibitor.

The …

Investigating The Antibacterial And Immunomodulatory Properties Of Lactobacillus Acidophilus Postbiotics, Rachael M. Wilson

Graduate School of Biomedical Sciences Theses and Dissertations

Probiotics are nonpathogenic microorganisms that have been extensively studied for their ability to prevent various infectious, gastrointestinal, and autoimmune diseases. The mechanisms underlying these probiotic effects have not been elucidated. However, we and other researchers have evidence suggesting that probiotic bacteria secrete metabolites that are antimicrobial and anti-inflammatory. As such, we developed a methodology to collect the secreted metabolites from a probiotic bacterium, Lactobacillus acidophilus, and tested this cell free filtrate (CFF) both in vitro and in vivo. Using this CFF, we have demonstrated that L. acidophilus secretes a molecule(s) that has specific bactericidal activity against the opportunistic pathogen, Pseudomonas …

Lipoxin A 4 (Lxa 4 ) Promotes Reduction And Antibiotic Efficacy Against Pseudomonas Aeruginosa Biofilm, Julianne M. Thornton, Jean Walker, Prem Yugandhar Kadiyam Sundarasivarao, Bernd Spur, Ana Rodriguez, Kingsley Yin

Rowan-Virtua Research Day

Pseudomonas aeruginosa (P aeruginosa) is an opportunistic bacterium commonly found in wound infections and airways of cystic fibrosis patients P aeruginosa readily forms biofilms which can reduce the efficacy of antibiotics used to eradicate the pathogen We have previously shown that a Specialized Pro resolving Mediator ( Lipoxin A 4 (LxA 4 is a quorum sensing inhibitor which can reduce P aeruginosa virulence In this study, we examined the direct actions of LxA 4 and RvD 2 on P aeruginosa biofilm formation and virulence gene expression The influence of LxA 4 on antibiotic efficacy and the combined effects on biofilm …

Mechanism Of Translation Inhibition By Type Ii Gnat Toxin Atat2, Stepan V Ovchinnikov, Dmitry Bikmetov, Alexei Livenskyi, Marina Serebryakova, Brendan Wilcox, Kyle Mangano, Dmitrii I Shiriaev, Ilya A Osterman, Petr V Sergiev, Sergei Borukhov, Nora Vazquez-Laslop, Alexander S Mankin, Konstantin Severinov, Svetlana Dubiley

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Type II toxin-antitoxins systems are widespread in prokaryotic genomes. Typically, they comprise two proteins, a toxin, and an antitoxin, encoded by adjacent genes and forming a complex in which the enzymatic activity of the toxin is inhibited. Under stress conditions, the antitoxin is degraded liberating the active toxin. Though thousands of various toxin-antitoxins pairs have been predicted bioinformatically, only a handful has been thoroughly characterized. Here, we describe the AtaT2 toxin from a toxin-antitoxin system from Escherichia coli O157:H7. We show that AtaT2 is the first GNAT (Gcn5-related N-acetyltransferase) toxin that specifically targets charged glycyl tRNA. In vivo, the AtaT2 …

Histidine-Triad Hydrolases Provide Resistance To Peptide-Nucleotide Antibiotics., Eldar Yagmurov, Darya Tsibulskaya, Alexey Livenskyi, Marina Serebryakova, Yury I Wolf, Sergei Borukhov, Konstantin Severinov, Svetlana Dubiley

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The Escherichia coli microcin C (McC) and related compounds are potent Trojan horse peptide-nucleotide antibiotics. The peptide part facilitates transport into sensitive cells. Inside the cell, the peptide part is degraded by nonspecific peptidases releasing an aspartamide-adenylate containing a phosphoramide bond. This nonhydrolyzable compound inhibits aspartyl-tRNA synthetase. In addition to the efficient export of McC outside the producing cells, special mechanisms have evolved to avoid self-toxicity caused by the degradation of the peptide part inside the producers. Here, we report that histidine-triad (HIT) hydrolases encoded in biosynthetic clusters of some McC homologs or by standalone genes confer resistance to McC-like …

The Effect Of Intracellular Zinc Levels In Escherichia Coli On Metallo-Β-Lactamase Activity, Jill Thompson

Graduate School of Biomedical Sciences Theses and Dissertations

Antibiotic resistance is a consequence of evolution via natural selection and poses a serious threat to the world's population. Escherichia coli, and other bacterial species, have acquired genes encoding Metallo-β-Lactamases (MBLs). MBLs are zinc-dependent enzymes that degrade most β-lactam antibiotics, and have emerged as important antibacterial resistance determinants in multidrug resistant pathogens. There are several different families of MBLs, and the major clinically relevant ones are Verona Integrated-encoded Metallo-β-Lactamases (VIMs), Imipenemases (IMPs), and New Delhi Metallo-β-Lactamases (NDMs). These enzymes confer high level resistance to penicillins, cephalosporins, and carbapenems, and are not inhibited by FDA-approved β-lactamase inhibitors. Variants of NDM have …

Synthesis And Biological Activity Of Novel Quorum Sensing Compounds, Joseph Nicholas Capilato

Theses and Dissertations

Bacteria communicate with chemical signals in a process known as quorum sensing. This population density-dependent process involves the bacterial production, release and detection of structurally specific small molecules and enables the bacterial pathogen to regulate its virulence on a population-wide level. Using a variety of chemical and biological techniques, I have studied various quorum sensing systems in several bacteria, including Vibrio cholera and Pseudomonas aeruginosa. A key principle of this research involves the design, synthesis and testing of novel compounds for their biological activity. These molecules are typically based off of an initial lead target, which is often identified …

Bacterial Transcription Factors Grea, Greb And Dksa: Characterization Of Their Interaction With Rna Polymerase And Molecular Mechanism Of Action, Andrey Parshin

Graduate School of Biomedical Sciences Theses and Dissertations

The activity of RNA polymerase (RNAP), the key enzyme of transcription process, is regulated by a large number of transcription factors acting at each step of the transcription cycle. Our research project is focused on studying the structure and function of bacterial transcript cleavage factors GreA, GreB and the stringent response regulator DksA. Gre factors bind in the secondary channel of RNAP in backtracked (inactive) ternary elongation complexes and stimulate the enzyme's intrinsic RNase activity, which is required for suppression of transcription pause and arrest, enhancement of transcription fidelity, and efficient promoter escape. DksA also acts through the RNAP secondary …