Primary supervisor: Dr Ayesha Sabah Rahman, University of Leicester

Non-academic partner: Dr David Wyatt, Aston Particle Technologies Ltd

Project description

Anti-microbial resistance (AMR) is a global problem that presents significant challenge in treating infectious diseases. Pathogenesis of Pseudomonas aeruginosa is the outcome of complex interplay between resistance mechanisms such as biofilm formation, efflux, and virulence determinants such as pigments and siderophores. Pseudomonas aeruginosa causes chronic infections in cystic fibrosis and plays a prominent role in infections such as Non-cystic fibrosis bronchiectasis(NCFB), chronic wound infections, pneumonia and medical device related infections. In addition, P. aeruginosa is resistant to antibiotics such as β-lactams, aminoglycosides and fluoroquinolones. Therefore, there is an urgent need to develop novel multitargeted antimicrobial combinations effective against resistant strains.

Amino acids are naturally occurring substances and have multimodal mechanism of action. Optimal concentrations can increase drug solubility, permeability and can increase the potency and efficacy of existing antibiotics through synergistic activity (1).

Work from our group has shown that amino acids in combination with the model antibiotic ciprofloxacin provide enhanced anti-microbial activity compared to antibiotic alone in S. aureus(2). Inclusion of D-glutamic and D-aspartic acid resulted in a significant reduction in biofilm density as amino acids bind to eDNA leading to weakening and ultimately disrupting the extracellular matrix. We have also shown that amino acids can modulate efflux pumps, reduce growth and pigment production in P. aeruginosa (3). The P. aeruginosa produced siderophore pyochelin is an important modulator of S. aureus/P. aeruginosa interaction in the wound environment (4). Due to the effect of D-amino acids on both species, it will be interesting to determine their potential impact on siderophore production. The proposed project will build on these findings and aims to explore the mechanistic basis for antimicrobial activity of dry coated particles. Time course analysis of biofilm disruption and characterization of EPS matrix, genomic investigation of virulence factors using qPCR will provide a screening tool to short list amino acids. Following this, dry coated particles with antibiotic drug candidates will be formulated to validate a multiprong approach by studying pigment production (Pyocyanin), siderophore formation (pyoverdine and pyochelin), membrane permeability and efflux pumps.

The student will gain a unique interdisciplinary opportunity to study the mechanistic modulation of dry coated particles by combining microbiological assays (biofilm assay, confocal microscopy, qPCR) with complementary biophysical measurements (surface energy, surface area) using inverse gas chromatography. The academic research group will provide a challenging research training experience within the context of a mutually beneficial research collaboration with Aston Particle Technologies (APT).

References

(1) Idrees M, Mohammad AR, Karodia N, Rahman A. Multimodal Role of Amino Acids in Microbial Control and Drug Development. Antibiotics (Basel) 2020;9(6).

(2) Warraich AA, Mohammed AR, Perrie Y, Hussain M, Gibson H, Rahman A. Evaluation of anti-biofilm activity of acidic amino acids and synergy with ciprofloxacin on Staphylococcus aureus biofilms. Sci Rep 2020;10(1):9021.

(3) Warraich AA, Mohammed AUR, Gibson H, Hussain M, Rahman AS. Acidic amino acids as counterions of ciprofloxacin: Effect on growth and pigment production in Staphylococcus aureus NCTC 8325 and Pseudomonas aeruginosa PAO1. PLoS One 2021;16(4):e0250705.

4. Jenul C, Keim KC, Jens JN, Zeiler MJ, Schilcher K, Schurr MJ, Phelan VV, Horswill AR. Pyochelin biotransformation by Staphylococcus aureus shapes bacterial competition with Pseudomonas aeruginosa in polymicrobial infections. Cell Rep. 2023;42(6):112540

Candidates are encouraged to contact Dr Ayesha Sabah Rahman ( ) or Dr Christian Jenul to discuss the project before applying if they wish to.