Recent advances in the understanding, detection and therapeutic targeting of bacterial recalcitrance.

Antibiotic resistance is a growing threat for modern medicine, making treatment of infectious diseases increasingly tedious. However, even non-resistant bacteria can survive treatment and cause recurrent infections. This phenomenon is often due to non-proliferating bacteria able to survive the treatment and to resume infection afterwards, also called recalcitrant bacteria. Bacterial recalcitrance, which encompasses tolerance and persistence, is defined by increased survival of bacteria in the presence of antimicrobial agents. In contrast to resistance, the mechanisms underlying recalcitrance are only partially understood. In this review, we summarise the recent advances in the understanding of recalcitrance, its detection, as well as anti-recalcitrance therapies that have been developed. Recalcitrance is thought to be caused by a reduction of bacterial metabolism, mostly driven by stringent and SOS responses, leading to bacterial dormancy. These dormant bacteria escape the action of many antibiotics, preventing the complete resolution of infection. However, strategies have been proposed to tackle recalcitrance. Recalcitrant bacteria are susceptible to drugs whose action is independent of metabolic activity, such as membrane-targeting compounds. Inhibitors blocking the entry of bacteria into dormancy or locking bacteria in a permanent state of dormancy could help avoid recurrence of the infection. Dormant bacteria could also be forced to resume growth through supply of nutrients or signalling molecules. A phage specifically targeting dormant bacteria was recently described and may be an important tool to fight bacterial recalcitrance. Recalcitrance has been neglected for a long time, being in the shadow of resistance. However, both phenomena need to be further investigated in the future to develop a complete array of antibacterial agents that will allow to permanently eradicate all types of bacterial infections.