Antibiotic Killing of Diversely Generated Populations of Nonreplicating Bacteria

Abstract

Nonreplicating bacteria are known to be (or at least commonly thought to be) refractory to antibiotics to which they are genetically susceptible. Here, we explore the sensitivity to killing by bactericidal antibiotics of three classes of nonreplicating populations of planktonic bacteria: (i) stationary phase, when the concentration of resources and/or nutrients are too low to allow for population growth; (ii) persisters, minority subpopulations of susceptible bacteria surviving exposure to bactericidal antibiotics; and (iii) antibiotic-static cells, bacteria exposed to antibiotics that prevent their replication but kill them slowly if at all, the so-called bacteriostatic drugs. Using experimental populations of Staphylococcus aureus Newman and Escherichia coli K-12 (MG1655) and, respectively, nine and seven different bactericidal antibiotics, we estimated the rates at which these drugs kill these different types of nonreplicating bacteria. In contrast to the common belief that bacteria that are nonreplicating are refractory to antibiotic-mediated killing, all three types of nonreplicating populations of these Gram-positive and Gram-negative bacteria are consistently killed by aminoglycosides and the peptide antibiotics daptomycin and colistin, respectively. This result indicates that nonreplicating cells, irrespectively of why they do not replicate, have an almost identical response to bactericidal antibiotics. We discuss the implications of these results to our understanding of the mechanisms of action of antibiotics and the possibility of adding a short-course of aminoglycosides or peptide antibiotics to conventional therapy of bacterial infections.

Joint antibiotic and phage therapy: addressing the limitations of a seemingly ideal phage for treatingStaphylococcus aureusinfections

“…(iv) PYO Sa does not replicate on stationary phase S. aureus. In infected hosts, many of the bacteria will not be replicating, and thereby, phage would be particularly effective for treatment if they, like some antibiotics [31], could kill non-replicating S. aureus.…”

Parallel evolution of tobramycin resistance across species and environments

“…Aminoglycosides are actively transported into the cell following binding to the outer membrane, and subsequently can cause cell death by binding the 30S ribosome and blocking translation (Kohanski et al, 2010). They have also been shown to kill by binding to the outer membrane (Bulitta et al, 2015), and induce killing of cells that are not actively dividing (McCall et al, 2019).…”

A data-based mathematical modelling study to quantify the effects of ciprofloxacin and ampicillin on the within-host dynamics of Salmonella enterica during treatment and relapse

“…5 Bacterial migration from the liver to the blood m7. 5 Bacterial migration from the MLN to the blood m8. 5 Bacterial migration from the spleen to the blood m6.7…”

“…The effect of different antibiotics on bacterial dynamics has been studied extensively in vitro, in optimally and homogeneously growing bacterial populations harvested from exponentially growing cultures [5]. Conclusions drawn from these studies provide insights into the mode of action of different antibiotic agents on their bacterial targets; however, their clinical relevance remains unknown, as in vivo bacterial populations are characterised by heterogeneity in their growth and dissemination dynamics [6][7][8][9].…”

“…However, in vitro studies with Escherichia coli and Staphylococcus aureus have revealed that even though different antibiotic classes are homogeneously effective on exponential phase bacteria, they exert heterogeneous effects on slowly-replicating and non-replicating bacterial populations. Depending on which bacterial functions they target, different antibiotic classes are more or less active against slowor non-replicating bacteria [5,[23][24][25].…”