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

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 o...

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Published inbioRxiv : the preprint server for biology
Main Authors Hernandez, Daniella M, Marzouk, Melissa, Cole, Madeline, Fortoul, Marla C, Kethireddy, Saipranavi Reddy, Contractor, Rehan, Islam, Habibul, Moulder, Trent, Kalifa, Ariane R, Meneses, Estefania Marin, Mendoza, Maximiliano Barbosa, Thomas, Ruth, Masud, Saad, Pubien, Sheena, Milanes, Patricia, Diaz-Tang, Gabriela, Lopatkin, Allison J, Smith, Robert P
Format Journal Article
LanguageEnglish
Published United States 09.04.2024
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Abstract 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.
AbstractList 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.
Author Kalifa, Ariane R
Masud, Saad
Lopatkin, Allison J
Thomas, Ruth
Meneses, Estefania Marin
Moulder, Trent
Islam, Habibul
Mendoza, Maximiliano Barbosa
Cole, Madeline
Smith, Robert P
Hernandez, Daniella M
Kethireddy, Saipranavi Reddy
Marzouk, Melissa
Pubien, Sheena
Milanes, Patricia
Contractor, Rehan
Diaz-Tang, Gabriela
Fortoul, Marla C
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  organization: Department of Biological Sciences, Halmos College of Arts and Science, Nova Southeastern University, Fort Lauderdale, FL, 33314
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  organization: Department of Medical Education, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33314
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  organization: Department of Biological Sciences, Halmos College of Arts and Science, Nova Southeastern University, Fort Lauderdale, FL, 33314
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  organization: Department of Biomedical Engineering, University of Rochester Medical Center; Rochester, NY 14627; USA
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  givenname: Robert P
  surname: Smith
  fullname: Smith, Robert P
  organization: Department of Medical Education, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33314
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Snippet The inoculum effect has been observed for nearly all antibiotics and bacterial species. However, explanations accounting for its occurrence and strength are...
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Title Purine and pyrimidine synthesis differently affect the strength of the inoculum effect for aminoglycoside and β-lactam antibiotics
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