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.
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|Tremoulet, Adriana; Le, Jennifer; Poindexter, Brenda et al. (2014) Characterization of the population pharmacokinetics of ampicillin in neonates using an opportunistic study design. Antimicrob Agents Chemother 58:3013-20|
|Sinko, William; Wang, Yang; Zhu, Wei et al. (2014) Undecaprenyl diphosphate synthase inhibitors: antibacterial drug leads. J Med Chem 57:5693-701|
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|Sakoulas, George; Rose, Warren; Nonejuie, Poochit et al. (2014) Ceftaroline restores daptomycin activity against daptomycin-nonsusceptible vancomycin-resistant Enterococcus faecium. Antimicrob Agents Chemother 58:1494-500|
|Autmizguine, Julie; Moran, Cassie; Gonzalez, Daniel et al. (2014) Vancomycin cerebrospinal fluid pharmacokinetics in children with cerebral ventricular shunt infections. Pediatr Infect Dis J 33:e270-2|
|Sakoulas, George; Okumura, Cheryl Y; Thienphrapa, Wdee et al. (2014) Nafcillin enhances innate immune-mediated killing of methicillin-resistant Staphylococcus aureus. J Mol Med (Berl) 92:139-49|
|Bayer, Arnold S; Mishra, Nagendra N; Sakoulas, George et al. (2014) Heterogeneity of mprF sequences in methicillin-resistant Staphylococcus aureus clinical isolates: role in cross-resistance between daptomycin and host defense antimicrobial peptides. Antimicrob Agents Chemother 58:7462-7|
|Liu, Yan; Haste, Nina M; Thienphrapa, Wdee et al. (2014) Marinopyrrole derivatives as potential antibiotic agents against methicillin-resistant Staphylococcus aureus (III). Mar Drugs 12:2458-70|
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