Multidrug tolerance
Encyclopedia
Multidrug tolerance or antibiotic tolerance is the ability of a disease-causing microorganism
to resist killing by antibiotic
s or other antimicrobial
s. 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
.
will develop. 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.
s, and it has been suggested that this is the reason that makes biofilm-related diseases so hard to treat. Examples are chronic infections of implanted
medical devices such as catheter
s and artificial joints, urinary tract infection
s, middle ear infections
and fatal lung disease (cystic fibrosis
).
. Multidrug tolerant persister cells are not antibiotic resistant
mutants. Resistance is caused by newly acquired genetic traits (by mutation or horizontal gene transfer
) that are heritable
and confer the ability to grow at elevated concentrations of antimicrobial drugs. In contrast, multidrug tolerance is 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.
genetic switch, although inducible mechanisms of persister cell formation have been described. 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. coli
high persistence gene, commonly abbreviated as HipA.
, by "the generation of a proton
-motive force which facilitates aminoglycoside uptake".
Microorganism
A microorganism or microbe is a microscopic organism that comprises either a single cell , cell clusters, or no cell at all...
to resist killing by antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s or other antimicrobial
Antimicrobial
An anti-microbial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans. Antimicrobial drugs either kill microbes or prevent the growth of microbes...
s. It is mechanistically distinct from multidrug resistance: It is not caused by mutant
Mutant
In biology and especially genetics, a mutant is an individual, organism, or new genetic character, arising or resulting from an instance of mutation, which is a base-pair sequence change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or trait not...
microbes, but rather by microbial cells that exist in a transient, dormant
Dormancy
Dormancy is a period in an organism's life cycle when growth, development, and physical activity are temporarily stopped. This minimizes metabolic activity and therefore helps an organism to conserve energy. Dormancy tends to be closely associated with environmental conditions...
, non-dividing state. Microorganisms that display multidrug tolerance can be bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
, fungi
Pathogenic fungi
Pathogenic fungi are fungi that cause disease in humans or other organisms. The study of pathogenic fungi is referred to as medical mycology. Although fungi are eukaryotic organisms many pathogenic fungi are also microorganisms.-Candida:...
or parasites
Protozoa
Protozoa are a diverse group of single-cells eukaryotic organisms, many of which are motile. Throughout history, protozoa have been defined as single-cell protists with animal-like behavior, e.g., movement...
.
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 (refractory or tolerant) 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 infectionInfection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
will develop. 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 biofilmBiofilm
A biofilm is an aggregate of microorganisms in which cells adhere to each other on a surface. These adherent cells are frequently embedded within a self-produced matrix of extracellular polymeric substance...
s, and it has been suggested that this is the reason that makes biofilm-related diseases so hard to treat. Examples are chronic infections of implanted
Implant (medicine)
An implant is a medical device manufactured to replace a missing biological structure, support a damaged biological structure, or enhance an existing biological structure. Medical implants are man-made devices, in contrast to a transplant, which is a transplanted biomedical tissue...
medical devices such as catheter
Catheter
In medicine, a catheter is a tube that can be inserted into a body cavity, duct, or vessel. Catheters thereby allow drainage, administration of fluids or gases, or access by surgical instruments. The process of inserting a catheter is catheterization...
s and artificial joints, urinary tract infection
Urinary tract infection
A urinary tract infection is a bacterial infection that affects any part of the urinary tract. Symptoms include frequent feeling and/or need to urinate, pain during urination, and cloudy urine. The main causal agent is Escherichia coli...
s, middle ear infections
Otitis media
Otitis media is inflammation of the middle ear, or a middle ear infection.It occurs in the area between the tympanic membrane and the inner ear, including a duct known as the eustachian tube. It is one of the two categories of ear inflammation that can underlie what is commonly called an earache,...
and fatal lung disease (cystic fibrosis
Cystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
).
Distinction from multidrug resistance
Unlike resistance, multidrug tolerance is a transient, non-heritable phenotypePhenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
. Multidrug tolerant persister cells are not antibiotic resistant
Antibiotic resistance
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...
mutants. Resistance is caused by newly acquired genetic traits (by mutation or horizontal gene transfer
Horizontal gene transfer
Horizontal gene transfer , also lateral gene transfer , is any process in which an organism incorporates genetic material from another organism without being the offspring of that organism...
) that are heritable
Heredity
Heredity is the passing of traits to offspring . This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. Through heredity, variations exhibited by individuals can accumulate and cause some species to evolve...
and confer the ability to grow at elevated concentrations of antimicrobial drugs. In contrast, multidrug tolerance is 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
Progeny
Progeny can refer to:*A genetic descendant or offspring*An academic progeny Other uses*Progeny Linux Systems*Progeny - an episode of the television series Stargate Atlantis...
is sensitive
Antibiotic sensitivity
Antibiotic sensitivity is a term used to describe the susceptibility of bacteria to antibiotics. Antibiotic susceptibility testing is usually carried out to determine which antibiotic will be most successful in treating a bacterial infection in vivo. Testing for antibiotic sensitivity is often...
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 stochasticStochastic
Stochastic refers to systems whose behaviour is intrinsically non-deterministic. A stochastic process is one whose behavior is non-deterministic, in that a system's subsequent state is determined both by the process's predictable actions and by a random element. However, according to M. Kac and E...
genetic switch, although inducible mechanisms of persister cell formation have been described. 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. coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
high persistence gene, commonly abbreviated as HipA.
Potential treatment
In May 2011, it was reported by Nature.com that aminoglycosides can help suppress multidrug tolerance in numerous species of bacteria, including E. coli and S. aureusS. aureus
S. aureus may refer to:* Scleropages aureus, a proposed species of the Asian arowana, a fish species native to Southeast Asia* Senecio aureus, the golden ragwort, a perennial flowering plant species native to eastern North America...
, by "the generation of a proton
Proton
The proton is a subatomic particle with the symbol or and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number....
-motive force which facilitates aminoglycoside uptake".
See also
- Antibiotic resistanceAntibiotic resistanceAntibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...
- Antibiotic sensitivityAntibiotic sensitivityAntibiotic sensitivity is a term used to describe the susceptibility of bacteria to antibiotics. Antibiotic susceptibility testing is usually carried out to determine which antibiotic will be most successful in treating a bacterial infection in vivo. Testing for antibiotic sensitivity is often...
- BacteriaBacteriaBacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
- BiofilmBiofilmA biofilm is an aggregate of microorganisms in which cells adhere to each other on a surface. These adherent cells are frequently embedded within a self-produced matrix of extracellular polymeric substance...
- Chronic woundChronic woundA chronic wound is a wound that does not heal in an orderly set of stages and in a predictable amount of time the way most wounds do; wounds that do not heal within three months are often considered chronic....
- DormancyDormancyDormancy is a period in an organism's life cycle when growth, development, and physical activity are temporarily stopped. This minimizes metabolic activity and therefore helps an organism to conserve energy. Dormancy tends to be closely associated with environmental conditions...
- InfectionInfectionAn infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
- Infectious DiseaseInfectious diseaseInfectious diseases, also known as communicable diseases, contagious diseases or transmissible diseases comprise clinically evident illness resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism...
- Multidrug resistanceMultidrug resistanceMultiple drug resistance or Multidrug resistance is a condition enabling a disease-causing organism to resist distinct drugs or chemicals of a wide variety of structure and function targeted at eradicating the organism...
- PathogenPathogenA pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
- RelapseRelapseRelapse, in relation to drug misuse, is resuming the use of a drug or a dependent substance after one or more periods of abstinence. The term is a landmark feature of both substance dependence and substance abuse, which are learned behaviors, and is maintained by neuronal adaptations that mediate...