Antimicrobial systems pharmacology
Systems pharmacology involves the characterisation of drug action at the whole-system level. In antimicrobial drug discovery and development, the system-wide impact of drug treatment on microbial pathogens can be measured with metabolomic, proteomic and transcriptomic approaches. These systems biology tools, combined with bioinformatics, statistical and mathematical modelling, allow the discovery of drug actions and reveal interactions between multiple pathways implicated in drug action, resistance or toxicity.
D4 researchers apply these omics technologies to in vitro systems and animals to describe molecular mechanisms and incorporate pharmacokinetic (PK), pharmacodynamic (PD), toxicodynamic (TD) and pharmacogenomic (PG) data to provide a multi-level systems understanding of antimicrobial pharmacology.
Systems pharmacology of polymyxins and combinations
Systems pharmacology has rarely been used by antimicrobial pharmacologists to evaluate antibiotic monotherapy and combination therapy. Systems pharmacology combines multiplex omics data with mathematical modelling to understand the dynamics and functions of biochemical networks in bacterial cells and the host.
Antibiotics at or below their minimal inhibitory concentrations affect dozens to hundreds of genes that relate to the complexities of antibiotic action or cellular-resistance responses. Understanding the mechanisms of action and PK/PD/TD of antibiotics using systems pharmacology is therefore critical to the development of novel strategies (such as combinations) to combat resistance.
Funded by the US National Institutes of Health, D4's research in this area employs platforms such as antimicrobial PK/PD/TD, microbiology, genomics, transcriptomics, proteomics, metabolomics, immunology and mathematical modelling to develop novel polymyxin combinations against multi-drug-resistant P. aeruginosa, A. baumannii and K. pneumoniae.
- Prof Jian Li
- Dr Tony Velkov
- Dr Darren Creek
Systems pharmacology of cell wall synthesis
Penicillin-binding proteins (PBPs) catalyse critical steps in the synthesis and remodelling of the bacterial cell wall. These enzymes are highly successful antibiotic targets. All bacteria have multiple PBP enzymes with different biochemical functions. The relationship between PBP binding and short-term bacterial viability has been assessed in E. coli, but such relationships are missing for essentially all other Gram-negative bacterial pathogens. Likewise, the relationships between PBP binding and emergence of bacterial resistance are largely unknown.
D4 researchers in this area are applying experimental and mathematical systems pharmacology approaches to establish the relationships between PBP binding, bacterial killing and emergence of resistance in critical Gram-negative bacteria. This research seeks to exploit these biological insights to rationally design and develop new antibiotics and mechanistically informed combination dosage regimens.
- Dr Jurgen Bulitta
- Dr Cornelia Landersdorfer
- Dr Tony Velkov
- Prof Roger Nation