Our current research deals with bacterial growth and death in infection-relevant settings. The role of the gut microbiota in host gastrointestinal (GI) tracts is manifold, one of which is its resilience to invasion by pathogenic species. The successful establishment of such pathogenic populations against a backdrop of large numbers of competing microorganisms is dependent on a number of environmental and host factors which can be altered by our modern use of antibiotics. As antibiotic use does not specifically target bacterial pathogens but rather the total microbiota, it is unclear how much such drugs contribute to the clearance of infections, and how much is as a result of the innate immune response. Studies in antimicrobial stewardship have rarely taken into account the effect of treatment regimen on the host microflora and immune response but often point to refractory subpopulations of bacteria, such as biofilms and microbial ‘persisters’, as drivers of recurrent and chronic infections in different infectious settings. We study the role of bacterial physiology in antimicrobial refractoriness using flowing systems or continuous cultures that mimic the pharmacokinetics of drugs in treated hosts. These studies are performed under conditions that are more reminiscent of the host environment where other species of bacteria reside, and compete, not only for resource but also antibiotic.

Basic mathematical models of pharmacodynamics / pharmacokinetics are used to predict the effect(s) of different compositions of this backdrop of microbiota and compared to the dynamics observed in the pathogen population. Using bacterial mutants that are deficient in different cellular pathways, we can deduce the relevance of specific genes to effective colonization and invasion of-, and persistence within our in vitro polymicrobial biome. This information can, in its own, turn to be used to approach the problem of treatment failure.

 

Selected publications

1) Abel Zur Wiesch, P., Abel, S., Gkotzis, S., Ocampo, P., Engelstädter, J., Hinkley, T., Magnus, C., Waldor, MK., Udekwu, K., Cohen, T. Classic reaction kinetics can explain complex patterns of antibiotic action. Sci Transl Med. 2015 May 13;7(287):287ra73

2) Alarcon, EI., Udekwu, KI., Noel, CW., Gagnon, LBP., Taylor, PK., Vulesevic, B. Simpson, MJ., Gkotzis, S., Islam, MM. Lee, CJ., Richter-Dahlfors, A., Mah, TF., Suuronen, EJ., Scaiano, JC., Griffith, M. Safety and efficacy of composite collagen-silver nanoparticle hydrogels as tissue engineering scaffolds. Nanoscale, 2015,7, 18789-18798

3) Levin, BR., Concepción-Acevedo, J., Udekwu, KI. Persistence: a copacetic and parsimonious hypothesis for the existence of non-inherited resistance to antibiotics. Curr Opin Microbiol. 2014 Oct;21:18-21.

4) Udekwu, KI., Levin, BR. Staphylococcus aureus in Continuous Culture: A Tool for the Rational Design of Antibiotic Treatment Protocols. PLoS One. 2012;7(7):e38866.

5) Levin, BR., Udekwu, KI. Population Dynamics of Antibiotic Treatment: a Mathematical Model and Hypotheses for Time-Kill and Continuous-Culture Experiments. Antimicrob Agents Chemother. 2010 Aug;54(8):3414-26.

 

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