Exploring the Influence of the metabolic pathways on the development of the colistin resistance in Salmonella Typhimurium

• Applicant: Dr. Mohammed Elbediwi, Ph.D.
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Veterinary Medical Science
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 564996063

Antimicrobial resistance (AMR) is a pressing concern that poses a significant threat to global public health. The increasing prevalence of AMR bacterial infections has intensified the complexity of treating infections and have rendered many currently used antibiotics ineffective. It is expected that fatalities resulting from infections caused by MDR pathogens will constitute the largest proportion of global deaths in the near future. AMR among Salmonella serovars particularly Typhimurium has risen substantially in the past decades and become a global public health concern. AMR S. Typhimurium has become a foremost concern in the animal breeding sector and in public health care. The dramatic increase of the AMR globally, necessitates the exploration of alternative strategies to combat MDR microbial infections. Recently, antimicrobial peptides (AMPs) have gained substantial attention as possible replacements to conventional antibiotics. Colistin (polymyxin E), a polycationic AMP discovered in 1949, has regained prominence as a "last-resort" antibiotic for treating severe infections caused by carbapenem-resistant bacteria in hospitalized patients. The emergence of colistin resistance poses a serious global health threat due to its crucial role in treating MDR bacterial infections. Resistance to colistin primarily arises through modifications to the bacterial outer membrane, particularly via mutations in genes involved in lipopolysaccharide (LPS) modification, such as mcr-1, pmrAB, and phoPQ. While the mechanisms of colistin resistance, lipid A modifications, are well-established, the underlying metabolic pathways driving the colistin resistance remain largely unexplored. Understanding the metabolic pathways involved in AMP resistance could therefore be significant for the development of new strategies to combat MDR bacterial infections. The main aim of this project is to examine the potential relationship between (fucR, punC, and lysR) metabolic genes and the development of the colistin resistance, that identified in my previous own work, focusing on their impact on various aspects of resistance, particularly on lipid A biosynthesis. Specifically, I aim to characterize the impact of fucR, punC, and lysR mutations on colistin susceptibility by generating mutant strains of S. Typhimurium and assess their colistin susceptibility profiles. Furthermore, I aim to address the potential changes in the evolutionary trajectories, changes in lipids structure and fitness cost in both aerobic and anaerobic conditions between the wild and mutated isolates. Finally, I aim to investigate the genetic transcriptional response of the wild-type and mutated isolates to colistin exposure through performing RNA-seq analysis. By investigating this correlation, I aim to identify novel targets for therapeutic intervention and develop strategies to aid in combating colistin-resistant infections.

• DFG Programme: WBP Position