Bacterial Heterogeneity and Antibiotic Survival: Understanding and Combatting Persistence and Heteroresistance

Abstract

For decades, mankind has dominated the battle against bacteria, yet the tide is slowly turning. Our antibacterial strategies are becoming less effective, allowing bacteria to get the upper hand. The alarming rise in antibiotic resistance is an important cause of anti-infective therapy failure. However, other factors are at play as well. It is widely recognized that bacterial populations display high levels of heterogeneity. Population heterogeneity generates phenotypes specialized in surviving antibiotic attacks. Nonetheless, the presence of antibiotic-insensitive subpopulations is not considered when initiating treatment. It is therefore time to reevaluate how we combat bacterial infections. We here focus on antibiotic persistence and heteroresistance, phenomena in which small fractions of the population are tolerant (persisters) and resistant to antibiotics, respectively. We discuss molecular mechanisms involved, their clinical importance, and possible therapeutic strategies. Moving forward, we argue that these heterogeneous phenotypes should no longer be ignored in clinical practice and that better diagnostic and therapeutic approaches are urgently needed.

Lyme Disease Frontiers: Reconciling Borrelia Biology and Clinical Conundrums

“…In contrast to antimicrobial resistance, the concept of persistence implies the survival, but not replication, of bacteria exposed to normally lethal concentrations of antibiotic [258]. It is a well-documented phenomenon for most pathogens, and has been associated with chronic infection (reviewed in [259]). In laboratory practice, persistence is characterized by a biphasic killing curve in which the bulk of the population is rapidly eliminated, and succeeded by a subpopulation of more tolerant cells with different kill kinetics [260].…”

Antibiotic resilience: a necessary concept to complement antibiotic resistance?

“…Sometimes, a minority of cells in isogenic populations is able to grow during antibiotic treatments. Because these cells are normally susceptible (unlike resistant cells) and are actively growing (unlike persisters), this phenomenon has been called 'phenotypic resistance', 'adaptive resistance' or 'heteroresistance' [35][36][37]55]. Phenotypic heterogeneity allows bacterial populations to adopt a 'bet-hedging' strategy in unpredictable environments, increasing the chances that a part of the population will survive disturbances such as antibiotic treatments [34,37,40].…”

Toxin/Antitoxin System Paradigms: Toxins Bound to Antitoxins Are Not Likely Activated by Preferential Antitoxin Degradation

“…However, there is little robust data regarding resuscitation from persisters due to inactivation of a TA system toxin. For example, it has been claimed incorrectly that the peptidyl-tRNA hydrolase Pth counteracts toxin TacT in Salmonella typhimurium during resuscitation, for example, by this passage [36] : "In Salmonella typhimurium persisters, tRNAs acetylated by the TacT toxin are deacetylated by the peptidyl-tRNA hydrolase Pth, reversing the effect of the toxin and allowing cells to resume growth," but there are no data showing Pth plays a role in persister resuscitation in the cited work. [37] Similarly, it has been claimed that deactivation of HokB toxin in E. coli controls persister waking; however, instead of single-cell observations, delays in resuscitation were estimated from growth data, [38] which are not direct proof of HokB inactivation in recovering persister cells.…”