Mechanisms of biofilms recalcitrance. Biofilm recalcitrance comprises a combination of antibiotic (ATB) resistance mechanisms (right panel) and ATB tolerance mechanisms (left panel). Resistance mechanisms confer the ability to survive and grow at increased ATB concentrations for long periods and involve horizontal genetic transfer (HGT), hypermutation, and quorum sensing (QS), leading to transport of antibiotics via efflux pumps, reduced permeability of the outer membrane, or production of enzymes that inactivate ATB. The type of AMR (Box 1) is indicated in green. In contrast, tolerance mechanisms lead microorganisms to survive at increased ATB concentrations temporally, and involve activation of stress responses (SOS response, stringent response SR)) and hypoxia, leading to activation of a quiescent state, anaerobic metabolism, decrease of membrane potential, and moderate increase in efflux pump expression. Arrowhead lines indicate the interrelation between mechanisms. CM: cytoplasmic membrane.