Antibiotic resistance and persistence—Implications for human health and treatment perspectives

Abstract

Antimicrobial resistance (AMR) and persistence are associated with an elevated risk of treatment failure and relapsing infections. They are thus important drivers of increased morbidity and mortality rates resulting in growing healthcare costs. Antibiotic resistance is readily identifiable with standard microbiological assays, and the threat imposed by antibiotic resistance has been well recognized. Measures aiming to reduce resistance development and spreading of resistant bacteria are being enforced. However, the phenomenon of bacteria surviving antibiotic exposure despite being fully susceptible, so‐called antibiotic persistence, is still largely underestimated. In contrast to antibiotic resistance, antibiotic persistence is difficult to measure and therefore often missed, potentially leading to treatment failures. In this review, we focus on bacterial mechanisms allowing evasion of antibiotic killing and discuss their implications on human health. We describe the relationship between antibiotic persistence and bacterial heterogeneity and discuss recent studies that link bacterial persistence and tolerance with the evolution of antibiotic resistance. Finally, we review persister detection methods, novel strategies aiming at eradicating bacterial persisters and the latest advances in the development of new antibiotics.

Ser/Thr phospho-regulation by PknB and Stp mediates bacterial quiescence and antibiotic persistence inStaphylococcus aureus

“…Besides skin and soft tissue infections (SSTI), S. aureus can cause severe and life-threatening, invasive infections such as endocarditis, osteomyelitis and bacteraemia 1 . Increasing levels of resistance against multiple antibacterial drugs, including penicillin, methicillin and vancomycin, render these infections difficult to treat and require prolonged treatment and extended hospitalization [3][4][5] .…”

Rapid and strain-specific resistance evolution ofStaphylococcus aureusagainst inhibitory molecules secreted byPseudomonas aeruginosa

“…The formation of SA SCVs is a well-known adaptive response towards stressful conditions (Kahl, Becker, and Löffler 2016), and we propose that SCVs evolved in our experiment as a response to PA inhibitory molecules such as HQNO (Hoffman et al 2006). Due to their slow metabolism, SCVs frequently exhibit reduced antibiotic susceptibility, which makes them particularly problematic in a clinical context (Huemer et al 2020). For 6850 clones, the strongest phenotypic changes involved increased STX production and better survival in the presence of oxidative stress (H2O2 exposure).…”

Occurrence of antimicrobial persistence in Streptococcus pyogenes

“…Phenotypic reversion was observed, indicating the involvement of non-inherited antimicrobial resistance mechanisms. Also, no mutation was detected in the persistent tiny colonies discarding the phenomenon of SVCs (Proctor, 2019;Huemer et al 2020). There is no question that bacterial resistance acquired through genetic mechanisms is the major reason for clinical failures during antimicrobial therapy for many other pathogens.…”

“…SCVs are characterized by their slow growth resulting in small colony sizes, which show mutations in genes often associated with auxotrophic phenotypes, electron transportation chain, and biosynthetic pathways (Proctor et al, 2006). Persistent bacteria occur in a subpopulation of cells capable of surviving in a phenotypic fashion at high concentrations of antimicrobials to which the bacteria are fully susceptible, with no change in the MIC (Huemer et al, 2020).…”