The defenses on this page work on drug concentration rather than on the drug or its target. Gram-negative bacteria have an outer membrane that a drug must cross, usually through water-filled channels called porins. Losing or mutating a porin reduces the rate at which the drug enters, and if the intracellular concentration never reaches the inhibitory threshold, the drug fails. Efflux pumps go further: these are membrane transporters that actively export the drug back out of the cell. Many clinically important pumps, such as the AcrAB-TolC system in Escherichia coli, span the inner membrane, the periplasm, and the outer membrane, and they accept a broad range of substrates. Because a single pump can recognize chemically unrelated molecules, efflux often produces simultaneous resistance to several classes, a phenotype called multidrug resistance. Porin loss and efflux are frequently combined, and the two effects multiply rather than simply add.
Bypass pathways evade the drug without touching it. Sulfonamides and trimethoprim block successive steps in bacterial folate synthesis, but a bacterium that acquires an alternative enzyme, or that can scavenge thymidine from its environment, can supply the needed metabolite by a route the drug does not inhibit. Biofilm tolerance is a different phenomenon: cells embedded in a biofilm matrix are protected partly by restricted drug penetration and partly by a slow-growing, metabolically quiet state in which the drug's target process is barely running. This is tolerance rather than classical resistance, because the cells are not genetically shielded and can become susceptible again when they disperse and resume growth.