Evolution of Bacterial Tolerance Under Antibiotic Treatment and Its Implications on the Development of Resistance

Abstract

Recent laboratory evolution studies have shown that upon repetitive antibiotic treatments, bacterial populations will adapt and eventually became tolerant and resistant to the drug. Drug tolerance rapidly evolves upon frequent, intermittent antibiotic treatments, and such emerging drug tolerance seems to be specific to the treatment conditions, complicating clinical practice. Moreover, it has been shown that tolerance often promotes the development of resistance, which further reinforces the need of clinical diagnostics for antibiotic tolerance to reduce the occurrence of acquired resistance. Here, we discuss the laboratory evolution studies that were performed to track the development of tolerance in bacterial populations, and highlight the urgency of developing a comprehensive knowledge base of various tolerance phenotypes and their detection in clinics. Finally, we propose future directions for basic research in this growing field.

Comparative proteomic investigation of multiple methicillin-resistant Staphylococcus aureus strains generated through adaptive laboratory evolution

“…Advancing technology will soon enable us to observe the cellular changes at the systems level in real-time and in finer resolution, as the bacteria adapt to different antibiotic treatments. Combined with the ALE strategy to generate diverse tolerant mutants, such large-scale studies should be our most direct path to comprehensively mapping the so-called “tolerome” ( Sulaiman and Lam, 2021 ; Brauner et al., 2016 ) and clarifying the mechanisms of tolerance. Overall, we believe that this study is a clear step forward in our effort to survey the landscape of genetic and metabolic changes that govern tolerance in S .…”

“…While resistance is characterized through an elevation in the MIC, a tolerant population is marked by the higher minimum duration for killing (MDK) as they have no change in the MIC compared to the susceptible population ( Brauner et al., 2016 ). Most of the previous studies that applied such in vitro evolution experiments to study tolerance and resistance only used a single drug ( Sulaiman and Lam, 2021 ), and the evolutionary trajectory of tolerance and resistance development under drug combinations remains unexplored. A recent study by Liu et al.…”

Novel Daptomycin Tolerance and Resistance Mutations in Methicillin-Resistant Staphylococcus aureus from Adaptive Laboratory Evolution

“…Bacterial populations can cope with and adapt to various stress conditions, including repetitive antibiotic treatment. The two known bacterial adaptation strategies toward antibiotics are resistance and tolerance ( 1 – 3 ). Resistance is more well studied; it directly counters the antibiotic’s action mechanism and allows bacteria to grow at an elevated antibiotic concentration, most often by directly inactivating the drug, altering the drug targets to reduce binding affinity, and decreasing uptake or increasing efflux ( 4 ).…”

“…We attribute this observation to the higher extent of killing in the exponential-phase culture compared to the stationary-phase one. At a dose of 10 mg/liter of daptomycin, the exponential-phase culture exhibits a steeper killing slope during the treatment and, consequently, a faster invasion of the resistant mutants during the repetitive treatment cycles ( 1 , 7 ). As previously reported, while daptomycin is strongly bactericidal against exponential-phase cells, it displays a concentration-dependent bactericidal activity against high-inoculum stationary-phase cells ( 24 ).…”

The Dynamic SecYEG Translocon

“…The rapid rise of antibiotic resistance is a major problem for treating infections and novel antimicrobial strategies are of crucial importance (Rodríguez-Rojas et al, 2013;Sulaiman and Lam, 2021). Initial studies on exploring the protein transport machinery as potential target were focused on SecA inhibitors, because SecA homologues are absent in metazoans and SecA inhibition would affect most periplasmic and OMPs as well as some inner membrane proteins (Pohlschroder et al, 2005).…”