Integrating rational design principles to develop resistance-limiting antibiotics for Gram-negative pathogens
  • Metaadatok
Tartalom: https://doktori.bibl.u-szeged.hu/id/eprint/13010/
Archívum: SZTE Doktori Értekezések Repozitórium
Gyűjtemény: Tudományterületek = Természettudományok: Biológiai tudományok
Típus = Disszertáció
Cím:
Integrating rational design principles to develop resistance-limiting antibiotics for Gram-negative pathogens
Létrehozó:
Maharramov Elvin
Dátum:
2026-03-31
Téma:
01.06.18.01. Rendszerbiológia
01.06.01.13. Mikrobiálos ökológia és fejlődés
01.06.01.01. Mikrobiológia
01.06.01.02. Bakteriológia
Tartalmi leírás:
Antibiotics that target multiple cellular functions are thought to be less susceptible to bacterial resistance. This thesis demonstrates that while dual-targeting strategies are essential, they are insufficient to prevent resistance. Instead, antibiotics that concurrently disrupt membrane integrity and inhibit an additional cellular pathway significantly reduce the development of resistance in Gram-negative ESKAPE pathogens, including Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. To test the hypothesis, we focused on three antibiotic candidates, POL7306, Tridecaptin M152-P3, and SCH79797, all of which meet the above criteria, and evaluated several factors that could limit the evolution of resistance. First, mutations arising de novo led to only marginal increases in resistance, with detailed functional analyses revealing that conventional resistance pathways were not readily accessible. Second, resistance through gene amplification was unreachable. Third, mobile genetic elements encoding resistance to these antibiotics were infrequent in human-associated microbiomes and clinically significant pathogens. Additionally, an exceptionally rapid eradication of bacterial populations was observed following exposure to membrane-targeting antibiotics at toxic concentrations. These findings suggest that naturally occurring resistance mechanisms in bacterial pathogens provide only limited protection against these antibiotics. These results offer critical insights and practical recommendations for designing next-generation antibiotics that are more resilient to resistance, ensuring long-term efficacy in combating multidrug-resistant pathogens.
Nyelv:
angol
angol
angol
Típus:
Disszertáció
NonPeerReviewed
Formátum:
text
text
Azonosító:
Maharramov Elvin Integrating rational design principles to develop resistance-limiting antibiotics for Gram-negative pathogens. Doktori értekezés, Szegedi Tudományegyetem (2000-). (2026)
Kapcsolat: