Understanding tolerance to cell wall–active antibiotics

Antibiotic tolerance-the ability of bacteria to survive for an extended time in the presence of bactericidal antibiotics-is an understudied contributor to antibiotic treatment failure. Herein, I review the manifestations, mechanisms, and clinical relevance of tolerance to cell wall-active (CWA) antibiotics, one of the most important groups of antibiotics at the forefront of clinical use. I discuss definitions of tolerance and assays for tolerance detection, comprehensively discuss the mechanism of action of β-lactams and other CWA antibiotics, and then provide an overview of how cells mitigate the potentially lethal effects of CWA antibiotic-induced cell damage to become tolerant. Lastly, I discuss evidence for a role of CWA antibiotic tolerance in clinical antibiotic treatment failure.