Multidrug tolerance or antibiotic tolerance is the ability of a disease-causing microorganism to resist being killed by antibiotics or other antimicrobials. It is mechanistically distinct from multidrug resistance: It is not caused by mutant microbes, but rather by microbial cells that exist in a transient, dormant, non-dividing state. Microorganisms that display multidrug tolerance can be bacteria, fungi or parasites.
History
Recognition of antibiotic tolerance dates back to 1944 when Joseph Bigger, an Irish physician working in England, was experimenting with the recently discovered penicillin. Bigger used penicillin to lyse a suspension of bacteria and then inoculated culture medium with the penicillin-treated liquid. Colonies of bacteria were able to grow after antibiotic killing. The important observation that Bigger made was that this new population could again be killed by penicillin except for a small residual population. Hence the residual organisms were not antibiotic resistant mutants but rather a subpopulation of what he called ‘persisters’. The formation of persisters is now known to be a common phenomenon that can occur by the formation of persister cells prior to the antibiotic treatment or in response to a variety of antibiotics.
Relevance to chronic infections
Multidrug tolerance is caused by a small subpopulation of microbial cells termed persisters. Persisters are not mutants, but rather are dormant cells that can survive the antimicrobial treatments that kill the majority of their genetically identical siblings. Persister cells have entered a non- or extremely slow-growing physiological state which makes them insensitive to the action of antimicrobial drugs. When such persisting microbial cells cannot be eliminated by the immune system, they become a reservoir from which recurrence of infection will develop. Such non-growing bacteria have been observed to persist within mammalian cells. Indeed, it appears that persister cells are the main cause for relapsing and chronic infections. Chronic infections can affect people of any age, health, or immune status.
Medical importance
Bacterial multidrug or antibiotic tolerance poses medically important challenges. It is largely responsible for the inability to eradicate bacterial infections with antibiotic treatment. Persister cells are highly enriched in biofilms, and it has been suggested that this is the reason that makes biofilm-related diseases so hard to treat. Examples are chronic infections of implantedmedical devices such as catheters and artificial joints, urinary tract infections, middle ear infections and fatal lung disease.
Unlike resistance, multidrug tolerance is a, non-heritable phenotype. Multidrug tolerant persister cells are not antibiotic resistant mutants. Resistance is caused by newly acquired genetic traits that are heritable and confer the ability to grow at elevated concentrations of antimicrobial drugs. In contrast, tolerant bacteria have the same MIC as susceptible bacteria and differ in the duration of the treatment that they can survive. Multidrug tolerance can be caused by a reversible physiological state in a small subpopulation of genetically identical cells, similar to a differentiated cell type. It enables this small subpopulation of microbes to survive the antibiotic killing of their surrounding siblings. Persisting cells resume growth when the antimicrobial agent is removed, and their progeny is sensitive to antimicrobial agents.
Molecular mechanisms
The molecular mechanisms that underlie persister cell formation and multidrug tolerance are largely unknown. Persister cells are thought to arise spontaneously in a growing microbial population by a stochastic genetic switch, although inducible mechanisms of persister cell formation have been described. For instance, Toxin-Antitoxin systems and a number of different stresses such as SOS-stress and envelope stress have been associated with persister formation. Owing to their transient nature and relatively low abundance, it is hard to isolate persister cells in sufficient numbers for experimental characterization, and only a few relevant genes have been identified to date. The best-understood persistence factor is the E. colihigh persistence gene, commonly abbreviated as hipA. Although tolerance is widely considered a passive state, there is evidence indicating it can be an energy-dependent process. Persister cells in E. coli can transport intracellular accumulations antibiotic using an energy requiring efflux pump called TolC. A persister subpopulation has also been demonstrated in budding yeastSaccharomyces cerevisiae. Yeast persisters are triggered in a small subset of unperturbed exponentially growing cells by spontaneously occurring DNA damage, which leads to the activation of a general stress response and protection against a range of harsh drug and stress environments. As a result of the DNA damage, yeast persisters are also enriched for random genetic mutations that occurred prior to the stress, and are unrelated to the stress survival
Potential treatment
In May 2011, it was reported by Nature.com that the addition of certain metabolites can help suppress multidrug tolerance in numerous species of bacteria, including E. coli and S. aureus, by "the generation of a proton-motive force which facilitates aminoglycoside uptake". Phage therapy, where applicable, entirely circumvents antibiotic tolerance.
