Reducing Inoculum Effect by Modulating Growth Productivity through the Superpathway of Purine, Pyrimidine and Histidine Synthesis in Escherichia coli
Abstract
Antibiotic overuse has driven the evolution of multiple antibiotic-resistant bacteria that complicate infections that were once easily treatable. While mechanisms by which individual bacterium resist or tolerate antibiotics are well explored, less studied are the mechanisms by which populations of bacteria tolerate antibiotics as a collective. One such mechanism bacteria employ to tolerate antibiotic treatment as a collective is the inoculum effect (IE). We recently discovered that growth productivity, which describes the relationship between ATP production and growth rate, can account for IE for multiple antibiotics and pathogens. However, the underlying pathways for determining growth productivity have yet to be discovered. To address this shortcoming, we used flux balance analysis coupled with a whole genome model of E. coli and OptKnock to quantify changes in growth productivity due to single gene removal in silico. We found an overrepresentation of genes related to purine and pyrimidine de novo synthesis and salvage. To assess the impact of this pathway on IE, we measured the IE of carbenicillin and streptomycin with exogenously added nitrogenous bases. We found significant correlations between the nitrogenous base-driven changes in ATP/growth rate and the strength of IE. Further model-guided experimental manipulation of de novo nucleotide synthesis provided additional support for the critical role of this pathway in IE. Our work details a mechanism by which bacteria can tolerate antibiotics as a collective and have implications in both infectious disease and the persistence of microbial populations in the presence of antibiotics.
Faculty Sponsors
Dr. Robert P. Smith
Project Type
Event
Location
Alvin Sherman Library
Start Date
4-3-2024 12:30 PM
End Date
4-4-2024 1:30 PM
Reducing Inoculum Effect by Modulating Growth Productivity through the Superpathway of Purine, Pyrimidine and Histidine Synthesis in Escherichia coli
Alvin Sherman Library
Antibiotic overuse has driven the evolution of multiple antibiotic-resistant bacteria that complicate infections that were once easily treatable. While mechanisms by which individual bacterium resist or tolerate antibiotics are well explored, less studied are the mechanisms by which populations of bacteria tolerate antibiotics as a collective. One such mechanism bacteria employ to tolerate antibiotic treatment as a collective is the inoculum effect (IE). We recently discovered that growth productivity, which describes the relationship between ATP production and growth rate, can account for IE for multiple antibiotics and pathogens. However, the underlying pathways for determining growth productivity have yet to be discovered. To address this shortcoming, we used flux balance analysis coupled with a whole genome model of E. coli and OptKnock to quantify changes in growth productivity due to single gene removal in silico. We found an overrepresentation of genes related to purine and pyrimidine de novo synthesis and salvage. To assess the impact of this pathway on IE, we measured the IE of carbenicillin and streptomycin with exogenously added nitrogenous bases. We found significant correlations between the nitrogenous base-driven changes in ATP/growth rate and the strength of IE. Further model-guided experimental manipulation of de novo nucleotide synthesis provided additional support for the critical role of this pathway in IE. Our work details a mechanism by which bacteria can tolerate antibiotics as a collective and have implications in both infectious disease and the persistence of microbial populations in the presence of antibiotics.
