Effect of tolerance on evolution of antibiotic resistance — under drug-combination therapy

Antimicrobial resistance clearly fits our theme (gene-environment interactions) in these GEITP pages. The environmental signal (to the bacterium) is a drug that threatens its survival; genes in the genome (along with epigenetic effects) respond to this threat by inducing a set of biochemical pathways that will neutralize the drug’s mechanism of action. Prior to development of antimicrobial

resistance, bacteria frequently develop enhanced antimicrobial tolerance (i.e. diminished response to a drug — which occurs when the drug is used repeatedly, and the genome ‘adapts’ to continued presence of the drug). [Antimicrobial resistance is the ability of a microbe to grow in an inhibitory concentration of a drug (usually an antibiotic), whereas drug tolerance denotes a reduced rate of antimicrobial killing.]

Combinations of antibiotic are often used to improve efficacy, as well as to prevent emergence of antibiotic resistance. However, it remains unclear if antibiotic combinations prevent the emergence of tolerance. Authors [see attached article & editorial] studied

sequential Staphylococcus aureus isolates — from patients treated with daptomycin (a cyclic lipopeptide that disrupts bacterial cell membrane function, causing rapid depolarization and loss of membrane potential, leading to inhibition of protein, DNA, and RNA synthesis, and microbial death) plus rifampin (inhibitor of bacterial DNA-dependent RNA polymerase, which blocks the polymerase subunit, deep within the DNA/RNA channel, facilitating direct inhibition of bacterial elongating RNA).

Evolution experiments have shown that drug tolerance evolves quickly under cyclic antibiotic treatments, and subsequently promotes evolution of antibiotic resistance. In contrast to drug resistance mutations — that decrease effectiveness of the antibiotic and elevate the minimum inhibitory concentration (MIC), tolerance mutations increase the minimum time to kill the population — without altering the MIC. To understand whether the evolutionary trajectory of evolving tolerance — and thereafter resistance — occurs in patients, authors [see attached article] followed sequential isolates of life-threatening methicillin-resistant Staphylococcus aureus (MRSA) blood infections, in which bacterial infection persisted for at least 2 weeks, despite antibiotic treatment.

Authors detected rapid emergence of “tolerance” mutations, followed by the emergence of resistance — despite the combination treatment. This study, on clinical strains in vitro, revealed a new way by which (initial) tolerance promotes evolution of resistance under combination treatments. Further experiments under different antibiotic classes (see attached article] revealed the generality of the effect. Authors concluded that tolerance is an important factor to consider — in designing combination treatments that

prevent the evolution of drug resistance. Although this combination of antibiotics delayed emergence of tolerant populations, once tolerance was established, benefits of combination therapy in preventing resistance were lost. ☹


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