Aksoy, Cemile Selin
(2024)
Metabolic functions of the Pseudomonas aeruginosa aminoglycoside resistance gene, aph.
PhD thesis, University of Nottingham.
Abstract
Various factors contribute to the pathogenicity of Pseudomonas aeruginosa, an opportunistic pathogen responsible for severe infections, particularly in immunocompromised individuals. Among these factors, multidrug resistance stands out as a significant concern. The aph gene, chromosomally encoded in P. aeruginosa, plays a pivotal role in conferring resistance to kanamycin, an aminoglycoside class antibiotic. A study on the aph gene, highlighted the effect of the carbon source 4-HPA on aph transcription, suggesting a link between kanamycin resistance and metabolic processes. This finding underlines the need to explore alternative metabolic pathways associated with the aph resistance gene. Understanding these associations could pave the way for the development of novel antimicrobial strategies targeting aph associated pathways in bacterial metabolism. Therefore, the current study aimed to uncover the metabolic associations of the aph antibiotic resistance gene within P. aeruginosa.
Initial findings have revealed that aph, besides its role in resistance, impacts bacterial growth under oxygen limited conditions, potentially imposing a metabolic burden on the cells. Further investigations into the regulation of aph have uncovered the involvement of various transcriptional factors, including LasR, ToxR, and the signal c-di-GMP. These factors exert control over aph expression through complex signalling pathways, implicating aph in the broader context of virulence and adaptation. Indeed, aph has shown an impact on pyocyanin production via PqsE, coded by the fifth gene of the pqs operon. Transcriptomic analyses have demonstrated that aph affects the expression of genes involved in virulence factors, biofilm formation, and iron utilization, highlighting its potentially multifaceted role in P. aeruginosa pathogenesis. This suggests that targeting aph could not only reverse antibiotic resistance but also disrupt bacterial metabolism, impairing the pathogen's ability to cause infection.
In conclusion, aph represents a potential target for combating multidrug-resistant P. aeruginosa infections. By elucidating its role in bacterial metabolism and virulence, promising antimicrobial strategies for restoring the activity of kanamycin class aminoglycosides could be developed, facilitating effective strategies combatting lethal infections caused by P. aeruginosa.
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