Mathematical modelling highlights the potential for genetic manipulation as an adjuvant to counter efflux-mediated MDR in salmonella

George Youlden, Helen E McNeil, Jessica M A Blair, Sara Jabbari, John R King

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Abstract

Bacteria have developed resistance to antibiotics by various mechanisms, notable amongst these is the use of permeation barriers and the expulsion of antibiotics via efflux pumps. The resistance-nodulation-division (RND) family of efflux pumps is found in Gram-negative bacteria and a major contributor to multidrug resistance (MDR). In particular, Salmonella encodes five RND efflux pump systems: AcrAB, AcrAD, AcrEF, MdsAB and MdtAB which have different substrate ranges including many antibiotics. We produce a spatial partial differential equation (PDE) model governing the diffusion and efflux of antibiotic in Salmonella, via these RND efflux pumps. Using parameter fitting techniques on experimental data, we are able to establish the behaviour of multiple wild-type and efflux mutant Salmonella strains, which enables us to produce efflux profiles for each individual efflux pump system. By combining the model with a gene regulatory network (GRN) model of efflux regulation, we simulate how the bacteria respond to their environment. Finally, performing a parameter sensitivity analysis, we look into various different targets to inhibit the efflux pumps. The model provides an in silico framework with which to test these potential adjuvants to counter MDR.

Original languageEnglish
Article number56
Number of pages38
JournalBulletin of Mathematical Biology
Volume84
Issue number5
DOIs
Publication statusPublished - 5 Apr 2022

Bibliographical note

Funding Information:
SJ gratefully acknowledges support from the Biotechnology and Biological Sciences Research Council (Grant Code: BB/M021386/1). GHY is supported by an Engineering and Physical Sciences Doctoral Training Partnership award (EP/N509590/1). GHY was funded through a joint University of Birmingham and University of Nottingham scholarship. HEM and JMAB were funded by a BBSRC David Phillips fellowship to JMAB (BB/M02623X/1). All numerical solutions were computed in MATLAB R2019b (The MathWorks, Inc.). The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Funding Information:
SJ gratefully acknowledges support from the Biotechnology and Biological Sciences Research Council (Grant Code: BB/M021386/1). GHY is supported by an Engineering and Physical Sciences Doctoral Training Partnership award (EP/N509590/1). GHY was funded through a joint University of Birmingham and University of Nottingham scholarship. HEM and JMAB were funded by a BBSRC David Phillips fellowship to JMAB (BB/M02623X/1). All numerical solutions were computed in MATLAB R2019b (The MathWorks, Inc.). The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Publisher Copyright:
© 2022, The Author(s).

Keywords

  • Salmonella
  • Efflux pumps
  • Resistance-nodulation-division
  • Mathematical modelling
  • Parameter fitting

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