Project II: Drug-Drug Interactions Between Pharmaceutical and Endogenous Antibiotics Antimicrobial peptides (AMPs) are """"""""natural antibiotics"""""""" produced by leukocytes, epithelial cells, and platelets in response to infection. Our laboratory has studied the critical role of endogenous AMPs in defense against invasive bacterial infection, and characterized mechanisms by which leading bacterial pathogens display relative resistance to AMP killing. Their significance of AMPs in innate defense is magnified in the youngest age groups because of quantitative and qualitative defects in antibody and cellular immune responses. Recently we have discovered striking evidence of interactions between common antibiotics used in clinical practice and endogenous AMPs - such that particular antibiotics markedly decrease or increase bacterial AMP susceptibility. Effectively, different antibiotics appear to work in concert with, or at odds with, with our own innate immune system in killing important bacterial pathogens such as Staphylococcus aureus. For example, showed that bacteriostatic antibiotics including erythromycin, TMP-SFX, or chloramphenicol markedly reduced the susceptibility of several Gram+ or Gram- bacterial pathogens to diverse AMPs, resulting in true antagonism. In other research, we have identified novel mechanisms by which different beta-lactam antibiotics can increased the susceptibility of drug-resistant pathogens like MRSA and VRE to AMPs, resulting in true synergy. We hypothesize that interactions between pharmaceutical and endogenous antibiotics have important pharmacodynamic effects and implications for clinical infectious disease therapy. Thus this project proposes an entirely new approach in antibiotic pharmacology: the careful analysis of potential drug:drug interactions between pharmaceutical antibiotics and critical host AMPs in therapy of common bacterial infections in children .
In Aim 1 will identify synergistic and antagonistic drug:drug interactions between leading pharmaceutical antibiotics and four distinct human AMPs. against leading pediatric bacterial pathogens.
In Aim 2, we define developmental and organ-specific parameters of the endogenous pharmacodynamic response of cathelicidin AMPs.
In Aim 3, we probe the mechanistic basis for antibiotic:AMP synergy vs. drug-resistant Gram+ pathogens. This project has the potential to shift paradigms in a way that is immediately translational to the clinical setting, since we are studying drug:drug interactions between widely used clinically approved antibiotics with those antibiotics that nature gave us.
Our body makes natural antibiotics called antimicrobial peptides (AMPs) in response to infection that are critical in pathogen clearance. We have discovered that different commonly prescribed pharmaceutical antibiotics can either inhibit or enhance the activity of these endogenous AMPs. This project studies the developmental pharmacology of drug:drug interactions between antibiotics and AMPs to inform more affective approaches to treatment of antibiotic-resistant pathogens in infants and children.
|Sakoulas, George; Kumaraswamy, Monika; Kousha, Armin et al. (2017) Interaction of Antibiotics with Innate Host Defense Factors against Salmonella enterica Serotype Newport. mSphere 2:|
|Sakoulas, George; Rose, Warren; Berti, Andrew et al. (2017) Classical ?-Lactamase Inhibitors Potentiate the Activity of Daptomycin against Methicillin-Resistant Staphylococcus aureus and Colistin against Acinetobacter baumannii. Antimicrob Agents Chemother 61:|
|Lin, Leo; Kim, Janie; Chen, Hope et al. (2016) Component Analysis of Multipurpose Contact Lens Solutions To Enhance Activity against Pseudomonas aeruginosa and Staphylococcus aureus. Antimicrob Agents Chemother 60:4259-63|
|Sakoulas, George; Olson, Joshua; Yim, Juwon et al. (2016) Cefazolin and Ertapenem, a Synergistic Combination Used To Clear Persistent Staphylococcus aureus Bacteremia. Antimicrob Agents Chemother 60:6609-6618|
|Hollands, Andrew; Corriden, Ross; Gysler, Gabriela et al. (2016) Natural Product Anacardic Acid from Cashew Nut Shells Stimulates Neutrophil Extracellular Trap Production and Bactericidal Activity. J Biol Chem 291:13964-73|
|Shoji, Kensuke; Bradley, John S; Reed, Michael D et al. (2016) Population Pharmacokinetic Assessment and Pharmacodynamic Implications of Pediatric Cefepime Dosing for Susceptible-Dose-Dependent Organisms. Antimicrob Agents Chemother 60:2150-6|
|Lam, Lisa H; Capparelli, Edmund V; Kurzrock, Razelle (2016) Association of concurrent acid-suppression therapy with survival outcomes and adverse event incidence in oncology patients receiving erlotinib. Cancer Chemother Pharmacol 78:427-32|
|Cole, Jason N; Nizet, Victor (2016) Bacterial Evasion of Host Antimicrobial Peptide Defenses. Microbiol Spectr 4:|
|Le, J; Dam, Q; Schweizer, M et al. (2016) Effects of vancomycin versus nafcillin in enhancing killing of methicillin-susceptible Staphylococcus aureus causing bacteremia by human cathelicidin LL-37. Eur J Clin Microbiol Infect Dis 35:1441-7|
|Martovetsky, Gleb; Bush, Kevin T; Nigam, Sanjay K (2016) Kidney versus Liver Specification of SLC and ABC Drug Transporters, Tight Junction Molecules, and Biomarkers. Drug Metab Dispos 44:1050-60|
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