Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections

Key Points When bacteria become quiescent (that is, slow growing or non-growing), they can avoid being killed by bactericidal antibiotics. This phenomenon extends the period of morbidity experienced by the patient and necessitates prolonged antibiotic treatment to achieve a cure. The effects of such bacteria are evident from several infections that typically contain these organisms, such as biofilm diseases, osteomyeletis and tuberculosis granuloma. In the first decade of the new millenium, the discovery and development of antibiotics that target the function of the membrane have provided new paradigms with which to combat persisting bacteria. In one approach, agents disorganize the structure and function of the membrane bilayer, causing subsequent multiple antibacterial effects in cells. Many of these membrane-active agents are reported to kill bacterial biofilms. Moreover, agents that inhibit the function of bacterial respiratory and redox enzymes, thereby causing membrane depolarization and energy depletion, have been shown to kill dormant Mycobacterium tuberculosis . The effects of membrane-active agents on quiescent cell types arise from the fact that all living bacteria require an intact, functional membrane and all living cells require energy to sustain their viability, even without growth. Our understanding of slow-growing or non-growing bacteria has improved, as well as our knowledge about the mechanisms of membrane-acting agents. There are many opportunities for obtaining new classes of drugs based on our current understanding of the mechanisms behind these antimicrobials, as well as many challenges. Infections involving slow-growing and persistent bacteria, including Mycobacterium tuberculosis and biofilms, are difficult to treat. Here, Hurdle and colleagues argue that developing antibiotics to target the bacterial membrane and membrane functions is a promising approach for the treatment for these difficult-to-treat infections. Persistent infections involving slow-growing or non-growing bacteria are hard to treat with antibiotics that target biosynthetic processes in growing cells. Consequently, there is a need for antimicrobials that can treat infections containing dormant bacteria. In this Review, we discuss the emerging concept that disrupting the bacterial membrane bilayer or proteins that are integral to membrane function (including membrane potential and energy metabolism) in dormant bacteria is a strategy for treating persistent infection