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Growth Productivity Determines the Inoculum Effect of Aminoglycosides in Pseudomonas aeruginosa

Author

Gabriela Diaz-Tang, Nova Southeastern UniversityFollow

Defense Date

7-24-2023

Document Type

Thesis - NSU Access Only

Degree Type

Master of Science

Degree Name

Biological Sciences

First Advisor

Robert P. Smith, Ph.D.

Second Advisor

Omar T. Eldakar, Ph.D.

Third Advisor

Julie Torruellas Garcia, Ph.D.

Keywords

Growth productivity, inoculum effect, metabolism, growth rate, antibiotic tolerance, Pseudomonas aeruginosa

Abstract

The emergence of antibiotic resistance represents one of the greatest threats to global health in the 21st century. The issue is exacerbated by the slow development of new antibiotics to combat infections. Therefore, it is crucial to understand how bacterial populations can tolerate antibiotic treatment collectively to prevent the rampant evolution of antibiotic-resistant bacteria and develop novel approaches to extend the efficacy of existing antibiotics. One widely observed mechanism is the inoculum effect (IE), where antibiotic lethality decreases as the initial bacterial density increases. Previous research suggests that growth productivity, the relationship between growth and metabolism, can explain IE, but this has yet to be explored in Pseudomonas aeruginosa. Accordingly, we investigated the effect of five carbon sources across a wide range of equimolar amino acid concentrations on the metabolism, growth rate, and IE of P. aeruginosa. Our findings indicate that changes in nutrient availability impact both the growth productivity and IE in this pathogen. Specifically, differences in growth productivity can determine IE; when growth productivity increases, the average strength of IE for the aminoglycoside kanamycin decreases in P. aeruginosa. Thus, under optimal growth conditions, the density-dependent antibiotic tolerance of P. aeruginosa can be reduced. To further explore this relationship, we examined the ratio of log[ATP]/growth rate as a proxy for growth productivity for each carbon source and amino acid concentration combination. Our results suggest that this ratio can also predict IE. Notably, at an intermediate equimolar amino acid concentration of 0.0075 mM, when the ratio of log[ATP]/growth rate was sufficiently high, IE was effectively eliminated. Overall, our study highlights the importance of the growth environment in determining growth productivity and IE in P. aeruginosa. These insights may contribute to the development of novel strategies that reduce IE in the clinic without the need to increase antibiotic dosages to treat high-density P. aeruginosa infections.

Comments

This research was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and was accomplished under Grant Number R15AI159902

NSUWorks Citation

Gabriela Diaz-Tang. 2023. Growth Productivity Determines the Inoculum Effect of Aminoglycosides in Pseudomonas aeruginosa. Master's thesis. Nova Southeastern University. Retrieved from NSUWorks, . (140)
https://nsuworks.nova.edu/hcas_etd_all/140.