What’s the Matter with MICs: Bacterial Nutrition, Limiting Resources, and Antibiotic Pharmacodynamics

Berryhill, Brandon A; Gil-Gil, Teresa; Manuel, Joshua A; Smith, Andrew P.; Margollis, Ellie; Baquero, Fernando; Levin, Bruce R

doi:10.1128/spectrum.04091-22

Cited by 12 publications

(21 citation statements)

References 41 publications

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“…We found that even though these mutants are resistant, their growth rates and the maximum optical densities decreased proportionally to the drug concentration and their lag time was substantially increased (Supplemental Figure 4). This result is consistent with previous observations 15 .…”

Section: Resultssupporting

confidence: 94%

“…We exposed four independent cultures of ∼10 5 CFU/mL of E. coli MG1655 in glucose-limited minimal media to super-MIC (Minimum Inhibitory Concentration) concentrations of CHL and AZM for 30 days (Figure 1). The MIC of CHL and AZM with MG1655 were estimated by broth microdilution in this glucose-limited minimal media and found to be 6.25 ug/mL for both drugs 13 . Super-MIC concentrations of each drug that were shown to be bacteriostatic with minimal killing and/or growth were used in the experiment (Supplemental Figure 1).…”

Section: Resultsmentioning

confidence: 99%

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The Evolution of Heteroresistance via Small Colony Variants in Escherichia coli Following Long Term Exposure to Bacteriostatic Antibiotics

Gil-Gil,

Berryhill,

Manuel

et al. 2023

Preprint

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Traditionally, bacteriostatic antibiotics are agents able to arrest bacterial growth. Despite being unable to kill bacterial cells, when they are used clinically the outcome of these drugs is frequently as effective as when a bactericidal drug is used. We explore the dynamics ofEscherichia coliafter exposure to two ribosome-targeting bacteriostatic antibiotics, chloramphenicol and azithromycin, for thirty days. The results of our experiments provide evidence that bacteria exposed to these drugs replicate, evolve, and generate a sub-population of small colony variants (SCVs) which are resistant to multiple drugs. These SCVs contribute to the evolution of heteroresistance and rapidly revert to a susceptible state once the antibiotic is removed. Stated another way, exposure to bacteriostatic drugs selects for the evolution of heteroresistance in populations previously lacking this trait. More generally, our results question the definition of bacteriostasis as populations exposed to bacteriostatic drugs are replicating despite the lack of net growth.

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Section: Resultssupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

The Evolution of Heteroresistance via Small Colony Variants in Escherichia coli Following Long Term Exposure to Bacteriostatic Antibiotics

Gil-Gil,

Berryhill,

Manuel

et al. 2023

Preprint

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“…S3). These results are consistent with those previously observed for Escherichia coli [6], demonstrating that the results obtained previously are not restricted to Gram-negative bacteria.…”

Section: Resultssupporting

confidence: 93%

“…Previous studies have revealed that exposing E. coli to sub-inhibitory concentrations of antibiotics leads to decreasing both maximum growth rate and maximum optical density while increasing the lag phase of growth [6]. Our results here confirm this phenomenon applies to S. aureus as well.…”

Section: Discussionsupporting

confidence: 90%

“…Persistence is the fraction of quiescent bacterial cells that survive treatment with a super-inhibitory concentration of an antibiotic [5]. In a previous study with Escherichia coli , we have demonstrated that exposure to sub-inhibitory concentrations of antibiotics results in a decrease in the growth rate along with the maximum bacterial density achieved, as well as an increase in the lag phase (the time before the bacterial population begins to replicate) [6]; we confirm the generality of those findings here. Moreover, other studies have established that super-inhibitory antibiotic concentrations can elevate the mutation rate for resistance to other drugs [7] we have found that this phenomenon extends to sub-inhibitory antibiotic concentrations as well.…”

Section: Introductionmentioning

confidence: 99%

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The Tradeoffs Between Persistence and Mutation Rates at Sub-Inhibitory Antibiotic Concentrations inStaphylococcus aureus

Ismail,

Berryhill,

Gil-Gil

et al. 2024

Preprint

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The rational design of the antibiotic treatment of bacterial infections employs these drugs to reach concentrations that exceed the minimum needed to prevent the replication of the target bacteria. However, within a treated patient, spatial and physiological heterogeneity promotes antibiotic gradients such that the concentration of antibiotics at specific sites is below the minimum needed to inhibit bacterial growth. Here, we investigate the effects of sub-inhibitory antibiotic concentrations on three parameters central to bacterial infection and the success of antibiotic treatment, using in vitro experiments with Staphylococcus aureus and mathematical-computer simulation models. Our results, using drugs of six different classes, demonstrate that exposure to sub-inhibitory antibiotic concentrations not only alters the dynamics of bacterial growth but also increases the mutation rate to antibiotic resistance and decreases the rate of production of persister cells thereby reducing the persistence level. Understanding this trade-off between mutation rates and persistence levels resulting from sub-inhibitory antibiotic exposure is crucial for optimizing, and mitigating the failure of, antibiotic therapy.

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Evaluation of the in vitro effects of concentrations of antibiotics on three Enterobacteriaceae isolates

Delik,

Eroğlu,

Tefon-Öztürk

2024

World J Microbiol Biotechnol

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Due to the misuse and overuse of antibiotics, bacteria are now exposed to sub-minimum inhibitory concentrations (sub-MICs) of antibiotics in various environments. In recent years, exposure of bacteria to sub-MICs of antibiotics has led to the widespread emergence of antibiotic-resistant bacteria. In this study, three bacterial species from the Enterobacteriaceae family (Raoultella ornithinolytica, Pantoea agglomerans and Klebsiella quasivariicola) were isolated from water. The antibiotic susceptibility of these bacteria to 16 antibiotics was then investigated. The effects of sub-MICs of four selected antibiotics (kanamycin, chloramphenicol, meropenem, and ciprofloxacin) on the growth, biofilm formation, surface polysaccharide production, siderophore production, morphology, and expression of the translational/transcriptional regulatory transformer gene rfaH of these bacteria were analysed. The MICs of kanamycin, chloramphenicol, meropenem, and ciprofloxacin were determined to be 1, 2, 0.03 and 0.03 µg/mL for R. ornithinolytica; 0.6, 6, 0.03 and 0.05 µg/mL for P. agglomerans; and 2, 5, 0.04 and 0.2 µg/mL for K. quasivariicola. The growth kinetics and biofilm formation ability decreased for all three isolates at sub-MICs. The surface polysaccharides of R. ornithinolytica and P. agglomerans increased at sub-MICs. There was no significant change in the siderophore activities of the bacterial isolates, with the exception of MIC/2 meropenem in R. ornithinolytica and MIC/2 kanamycin in K. quasivariicola. It was observed that the sub-MICs of meropenem and ciprofloxacin caused significant changes in bacterial morphology. In addition, the expression of rfaH in R. ornithinolytica and K. quasivariicola increased with the sub-MICs of the selected antibiotics.

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What’s the Matter with MICs: Bacterial Nutrition, Limiting Resources, and Antibiotic Pharmacodynamics

Abstract: For studies of antibiotics and how they work, the most-often used measurement of drug efficacy is the MIC. The MIC is the concentration of an antibiotic needed to inhibit bacterial growth.

Cited by 12 publications

References 41 publications

The Evolution of Heteroresistance via Small Colony Variants in Escherichia coli Following Long Term Exposure to Bacteriostatic Antibiotics

The Evolution of Heteroresistance via Small Colony Variants in Escherichia coli Following Long Term Exposure to Bacteriostatic Antibiotics

The Tradeoffs Between Persistence and Mutation Rates at Sub-Inhibitory Antibiotic Concentrations inStaphylococcus aureus

Evaluation of the in vitro effects of concentrations of antibiotics on three Enterobacteriaceae isolates

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