Data for: 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. Previous work found that the relationship between
[ATP] and growth rate can account for the strength and occurrence of the
inoculum effect for bactericidal antibiotics. However, the molecular
pathway(s) underlying this relationship, and therefore determining the
inoculum effect, remain undiscovered. Using a combination of flux balance
analysis and experimentation, 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. If the
[ATP]/growth rate is sufficiently high as determined by exogenously
supplied nitrogenous bases, the inoculum effect does not occur. This is
consistent for both Escherichia coli and Pseudomonas aeruginosa.
Interestingly, 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 b-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, which may pave the way
for intervention strategies to reduce the inoculum effect in the clinic.