Purine and pyrimidine synthesis differently affect the strength of the inoculum effect for aminoglycoside and β-lactam antibiotics.

Autor:	Hernandez DM; Cell Therapy Institute, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33314., Marzouk M; Cell Therapy Institute, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33314.; Department of Biological Sciences, Halmos College of Arts and Science, Nova Southeastern University, Fort Lauderdale, FL, 33314., Cole M; Department of Medical Education, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33314., Fortoul MC; Department of Medical Education, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33314., Kethireddy SR; Department of Biological Sciences, Halmos College of Arts and Science, Nova Southeastern University, Fort Lauderdale, FL, 33314., Contractor R; Department of Biological Sciences, Halmos College of Arts and Science, Nova Southeastern University, Fort Lauderdale, FL, 33314., Islam H; Department of Chemical Engineering, University of Rochester; Rochester, NY 14627; USA., Moulder T; Department of Biological Sciences, Halmos College of Arts and Science, Nova Southeastern University, Fort Lauderdale, FL, 33314., Kalifa AR; Cell Therapy Institute, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33314.; Department of Biological Sciences, Halmos College of Arts and Science, Nova Southeastern University, Fort Lauderdale, FL, 33314., Meneses EM; Cell Therapy Institute, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33314.; Department of Biological Sciences, Halmos College of Arts and Science, Nova Southeastern University, Fort Lauderdale, FL, 33314., Mendoza MB; Cell Therapy Institute, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33314., Thomas R; Department of Biological Sciences, Halmos College of Arts and Science, Nova Southeastern University, Fort Lauderdale, FL, 33314., Masud S; Department of Medical Education, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33314., Pubien S; Department of Medical Education, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33314., Milanes P; Department of Medical Education, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33314., Diaz-Tang G; Cell Therapy Institute, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33314.; Department of Biological Sciences, Halmos College of Arts and Science, Nova Southeastern University, Fort Lauderdale, FL, 33314., Lopatkin AJ; Department of Chemical Engineering, University of Rochester; Rochester, NY 14627; USA.; Department of Microbiology and Immunology, University of Rochester Medical Center; Rochester, NY 14627; USA.; Department of Biomedical Engineering, University of Rochester Medical Center; Rochester, NY 14627; USA., Smith RP; Cell Therapy Institute, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33314.; Department of Medical Education, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33314.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Apr 09. Date of Electronic Publication: 2024 Apr 09.
DOI:	10.1101/2024.04.09.588696
Abstrakt:	The inoculum effect has been observed for nearly all antibiotics and bacterial species. However, explanations accounting for its occurrence and strength are lacking. We previously found that growth productivity, which captures the relationship between [ATP] and growth, can account for the strength of the inoculum effect for bactericidal antibiotics. However, the molecular pathway(s) underlying this relationship, and therefore determining the inoculum effect, remain undiscovered. We show that nucleotide synthesis can determine the relationship between [ATP] and growth, and thus the strength of inoculum effect in an antibiotic class-dependent manner. Specifically, and separate from activity through the tricarboxylic acid cycle, we find that transcriptional activity of genes involved in purine and pyrimidine synthesis can predict the strength of the inoculum effect for β-lactam and aminoglycosides antibiotics, respectively. Our work highlights the antibiotic class-specific effect of purine and pyrimidine synthesis on the severity of the inoculum effect and paves the way for intervention strategies to reduce the inoculum effect in the clinic. Competing Interests: Competing interests: All other authors declare they have no competing interests.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu