![WhatIsDrugResistance](https://upload.wikimedia.org/wikipedia/commons/5/54/WhatIsDrugResistance.gif)
Drug resistance is the reduction in effectiveness of a medication such as an
antimicrobial
An antimicrobial is an agent that kills microorganisms or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria, and antifungals ar ...
or an
antineoplastic in treating a
disease
A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
or condition. The term is used in the context of resistance that
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
s or cancers have "acquired", that is, resistance has evolved.
Antimicrobial resistance
Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...
and
antineoplastic resistance Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases, cancers can evolv ...
challenge clinical care and drive research. When an organism is resistant to more than one drug, it is said to be
multidrug-resistant.
The development of antibiotic resistance in particular stems from the drugs targeting only specific bacterial molecules (almost always proteins). Because the drug is ''so'' specific, any mutation in these molecules will interfere with or negate its destructive effect, resulting in antibiotic resistance. Furthermore, there is mounting concern over the abuse of antibiotics in the farming of livestock, which in the
European Union
The European Union (EU) is a supranational political and economic union of member states that are located primarily in Europe. The union has a total area of and an estimated total population of about 447million. The EU has often been des ...
alone accounts for three times the volume dispensed to humans – leading to development of super-resistant bacteria.
Bacteria are capable of not only altering the enzyme targeted by antibiotics, but also by the use of enzymes to modify the antibiotic itself and thus neutralize it. Examples of target-altering pathogens are ''
Staphylococcus aureus
''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive ...
'', vancomycin-resistant
enterococci
''Enterococcus'' is a large genus of lactic acid bacteria of the phylum Bacillota. Enterococci are gram-positive cocci that often occur in pairs (diplococci) or short chains, and are difficult to distinguish from streptococci on physical charac ...
and macrolide-resistant ''
Streptococcus
''Streptococcus'' is a genus of gram-positive ' (plural ) or spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales (lactic acid bacteria), in the phylum Bacillota. Cell division in streptococci occurs ...
'', while examples of antibiotic-modifying microbes are ''
Pseudomonas aeruginosa
''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. aerugi ...
'' and aminoglycoside-resistant ''
Acinetobacter baumannii
''Acinetobacter baumannii'' is a typically short, almost round, rod-shaped ( coccobacillus) Gram-negative bacterium. It is named after the bacteriologist Paul Baumann. It can be an opportunistic pathogen in humans, affecting people with compromi ...
''.
In short, the lack of concerted effort by governments and the pharmaceutical industry, together with the innate capacity of microbes to develop resistance at a rate that outpaces development of new drugs, suggests that existing strategies for developing viable, long-term anti-microbial therapies are ultimately doomed to failure. Without alternative strategies, the acquisition of drug resistance by pathogenic microorganisms looms as possibly one of the most significant public health threats facing humanity in the 21st century. Some of the best alternative sources to reduce the chance of antibiotic resistance are probiotics, prebiotics, dietary fibers, enzymes, organic acids, phytogenics.
Types
Drug, toxin, or chemical resistance is a consequence of
evolution
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
and is a response to pressures imposed on any living organism. Individual organisms vary in their sensitivity to the drug used and some with greater
fitness may be capable of surviving drug treatment. Drug-resistant traits are accordingly inherited by subsequent offspring, resulting in a population that is more drug-resistant. Unless the drug used makes sexual reproduction or
cell-division or
horizontal gene transfer
Horizontal gene transfer (HGT) or lateral gene transfer (LGT) is the movement of genetic material between Unicellular organism, unicellular and/or multicellular organisms other than by the ("vertical") transmission of DNA from parent to offsprin ...
impossible in the entire target population, resistance to the drug will inevitably follow. This can be seen in
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
ous tumors where some cells may develop resistance to the drugs used in
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
. Chemotherapy causes
fibroblasts
A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...
near
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s to produce large amounts of the protein
WNT16
Protein Wnt-16 is a protein that in humans is encoded by the ''WNT16'' gene. It has been proposed that stimulation of WNT16 expression in nearby normal cells is responsible for the development of chemotherapy-resistance in cancer cells.
Function ...
B. This protein stimulates the growth of cancer cells which are drug-resistant.
MicroRNA
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...
s have also been shown to affect acquired drug resistance in cancer cells and this can be used for therapeutic purposes.
Malaria
Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...
in 2012 has become a resurgent threat in
South East Asia
Southeast Asia, also spelled South East Asia and South-East Asia, and also known as Southeastern Asia, South-eastern Asia or SEA, is the geographical south-eastern region of Asia, consisting of the regions that are situated south of mainland ...
and
sub-Saharan Africa
Sub-Saharan Africa is, geographically, the area and regions of the continent of Africa that lies south of the Sahara. These include West Africa, East Africa, Central Africa, and Southern Africa. Geopolitically, in addition to the List of sov ...
, and drug-resistant strains of ''
Plasmodium falciparum
''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mosqu ...
'' are posing massive problems for health authorities.
Leprosy
Leprosy, also known as Hansen's disease (HD), is a long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the nerves, respiratory tract, skin, and eyes. This nerve damag ...
has shown an increasing resistance to
dapsone
Dapsone, also known as 4,4'-sulfonyldianiline (SDA) or diaminodiphenyl sulfone (DDS), is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. It is a second-line medication for the treatment a ...
.
A rapid process of sharing resistance exists among
single-celled organism
A unicellular organism, also known as a single-celled organism, is an organism that consists of a single cell, unlike a multicellular organism that consists of multiple cells. Organisms fall into two general categories: prokaryotic organisms an ...
s, and is termed horizontal gene transfer in which there is a direct exchange of genes, particularly in the
biofilm
A biofilm comprises any syntrophic consortium of microorganisms in which cells stick to each other and often also to a surface. These adherent cells become embedded within a slimy extracellular matrix that is composed of extracellular ...
state. A similar asexual method is used by
fungi
A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
and is called "
parasexuality
The parasexual cycle, a process restricted to fungi and single-celled organisms, is a nonsexual mechanism of parasexuality for transferring genetic material without meiosis or the development of sexual structures. It was first described by Italian ...
". Examples of drug-resistant strains are to be found in microorganisms such as bacteria and viruses, parasites both
endo- and
ecto-, plants, fungi,
arthropod
Arthropods (, (gen. ποδός)) are invertebrate animals with an exoskeleton, a Segmentation (biology), segmented body, and paired jointed appendages. Arthropods form the phylum Arthropoda. They are distinguished by their jointed limbs and Arth ...
s, mammals, birds, reptiles,
fish, and amphibians.
In the domestic environment, drug-resistant strains of organism may arise from seemingly safe activities such as the use of
bleach
Bleach is the generic name for any chemical product that is used industrially or domestically to remove color (whitening) from a fabric or fiber or to clean or to remove stains in a process called bleaching. It often refers specifically, to ...
, tooth-brushing and mouthwashing, the use of antibiotics, disinfectants and detergents,
shampoo
Shampoo () is a hair care product, typically in the form of a viscous liquid, that is used for cleaning hair. Less commonly, shampoo is available in solid bar format. Shampoo is used by applying it to wet hair, massaging the product into the ...
s, and soaps, particularly antibacterial soaps, hand-washing, surface sprays, application of
deodorant
A deodorant is a substance applied to the body to prevent or mask body odor due to bacterial breakdown of perspiration or vaginal secretions, for example in the armpits, groin, or feet. A subclass of deodorants, called antiperspirants, prevents ...
s,
sunblock
Sunscreen, also known as sunblock or sun cream, is a photoprotective topical product for the skin that mainly absorbs, or to a much lesser extent reflects, some of the sun's ultraviolet (UV) radiation and thus helps protect against sunburn and ...
s and any cosmetic or health-care product,
insecticide
Insecticides are substances used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. Insecticides are used in agriculture, medicine, industry and by consumers. Insecticides are claimed to b ...
s, and dips. The chemicals contained in these preparations, besides harming beneficial organisms, may intentionally or inadvertently target organisms that have the potential to develop resistance.
Mechanisms
The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are:
# Drug inactivation or modification: e.g., enzymatic deactivation of
''Penicillin'' G in some penicillin-resistant bacteria through the production of
β-lactamases.
# Alteration of target site: e.g., alteration of
PBP — the binding target site of penicillins — in
MRSA
Methicillin-resistant ''Staphylococcus aureus'' (MRSA) is a group of Gram-positive bacteria that are genetically distinct from other strains of ''Staphylococcus aureus''. MRSA is responsible for several difficult-to-treat infections in humans. ...
and other penicillin-resistant bacteria.
# Alteration of metabolic pathway: e.g., some
sulfonamide-resistant bacteria do not require
para-aminobenzoic acid
4-Aminobenzoic acid (also known as ''para''-aminobenzoic acid or PABA because the two functional groups are attached to the benzene ring across from one another in the ''para'' position) is an organic compound with the formula H2NC6H4CO2H. PABA ...
(PABA), an important precursor for the synthesis of
folic acid
Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...
and
nucleic acids
Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
in bacteria inhibited by sulfonamides. Instead, like mammalian cells, they turn to utilizing preformed folic acid.
# Reduced drug accumulation: by decreasing drug
permeability and/or increasing active
efflux (pumping out) of the drugs across the cell surface.
Mechanisms of Acquired Drug Resistance
Metabolic cost
''Biological cost'' is a measure of the increased
energy metabolism
Bioenergetics is a field in biochemistry and cell biology that concerns energy flow through living systems. This is an active area of biological research that includes the study of the transformation of energy in living organisms and the study of ...
required to achieve a function.
Drug resistance has a high metabolic price in pathogens for which this concept is relevant (bacteria, endoparasites, and tumor cells.) In viruses, an equivalent "cost" is genomic complexity. The high metabolic cost means that, in the absence of antibiotics, a resistant pathogen will have decreased evolutionary fitness as compared to susceptible pathogens. This is one of the reasons drug resistance adaptations are rarely seen in environments where antibiotics are absent. However, in the presence of antibiotics, the survival advantage conferred off-sets the high metabolic cost and allows resistant strains to proliferate.
Treatment
In humans, the gene
ABCB1
P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...
encodes
MDR1(p-glycoprotein) which is a key transporter of medications on the cellular level. If MDR1 is overexpressed, drug resistance increases.
Therefore, ABCB1 levels can be monitored.
In patients with high levels of ABCB1 expression, the use of secondary treatments, like metformin, have been used in conjunction with the primary drug treatment with some success.
For
antibiotic resistance
Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...
, which represents a widespread problem nowadays, drugs designed to block the mechanisms of bacterial antibiotic resistance are used. For example, bacterial resistance against
beta-lactam antibiotic
β-lactam antibiotics (beta-lactam antibiotics) are antibiotics that contain a beta-lactam ring in their chemical
structure. This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and ...
s (such as
penicillin
Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from ''Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum using ...
and
cephalosporin
The cephalosporins (sg. ) are a class of β-lactam antibiotics originally derived from the fungus ''Acremonium'', which was previously known as ''Cephalosporium''.
Together with cephamycins, they constitute a subgroup of β-lactam antibiotics ...
s) can be circumvented by using antibiotics such as
nafcillin
Nafcillin sodium is a narrow-spectrum beta-lactam antibiotic of the penicillin class. As a beta-lactamase-resistant penicillin, it is used to treat infections caused by Gram-positive bacteria, in particular, species of staphylococci that are res ...
that are not susceptible to destruction by certain
beta-lactamase
Beta-lactamases, (β-lactamases) are enzymes () produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems ( ertapenem), although carbap ...
s (the group of enzymes responsible for breaking down beta-lactams).
Beta-lactam bacterial resistance can also be dealt with by administering beta-lactam antibiotics with drugs that block beta-lactamases such as
clavulanic acid
Clavulanic acid is a β-lactam drug that functions as a mechanism-based β-lactamase inhibitor. While not effective by itself as an antibiotic, when combined with penicillin-group antibiotics, it can overcome antibiotic resistance in bacteria t ...
so that the antibiotics can work without getting destroyed by the bacteria first.
Recently, researchers have recognized the need for new drugs that inhibit
bacterial efflux pumps, which cause resistance to multiple antibiotics such as
beta-lactam
A beta-lactam (β-lactam) ring is a four-membered lactam. A ''lactam'' is a cyclic amide, and ''beta''-lactams are named so because the nitrogen atom is attached to the β-carbon atom relative to the carbonyl. The simplest β-lactam possible i ...
s,
quinolones
Quinolone may refer to:
* 2-Quinolone
* 4-Quinolone
4-Quinolone is an organic compound derived from quinoline. It and 2-quinolone are the two most important parent (meaning simplified) quinolones. 4-Quinolone exists in equilibrium with a mino ...
,
chloramphenicol, and
trimethoprim
Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers' diarrhea. With sulfamethoxazole or dapsone it may be used for ''Pneumocystis'' pneumonia in peo ...
by sending molecules of those antibiotics out of the bacterial cell. Sometimes a combination of different classes of antibiotics may be used synergistically; that is, they work together to effectively fight bacteria that may be resistant to one of the antibiotics alone.
Destruction of the resistant
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
can also be achieved by
phage therapy
Phage therapy, viral phage therapy, or phagotherapy is the therapeutic use of bacteriophages for the treatment of pathogenic bacterial infections. This therapeutic approach emerged at the beginning of the 20th century but was progressively re ...
, in which a specific
bacteriophage
A bacteriophage (), also known informally as a ''phage'' (), is a duplodnaviria virus that infects and replicates within bacteria and archaea. The term was derived from "bacteria" and the Greek φαγεῖν ('), meaning "to devour". Bacteri ...
(virus that kills bacteria) is used.
See also
*
Antibiotic resistance
Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...
*
Fecal bacteriotherapy
Fecal microbiota transplant (FMT), also known as a stool transplant, is the process of transferring fecal bacteria and other microbes from a healthy individual into another individual. FMT is an effective treatment for ''Clostridioides diffici ...
*
Mass drug administration
The administration of drugs to whole populations irrespective of disease status is referred to as mass drug administration (MDA).
This article describes the administration of antimalarial drugs to whole populations an intervention which has been u ...
*
Multidrug resistance
Multiple drug resistance (MDR), multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to at least one antimicrobial drug in three or more antimicrobial categories. Antimicrobial categories are c ...
*
Pharmacoepidemiology
Pharmacoepidemiology is the study of the uses and effects of drugs in well-defined populations.Porta M, editor. Greenland S, Hernán M, dos Santos Silva I, Last JM, associate editors (2014). "A dictionary of epidemiology", 6th. edition. New York: O ...
*
Physical factors affecting microbial life
*
Small multidrug resistance protein
Small multidrug resistance protein (also known as Drug/Metabolite Transporter) is a family of integral membrane proteins that confer drug resistance to a wide range of toxic compounds by removing them for the cells. The efflux is coupled to an i ...
* ''
Eleftheria terrae
''Eleftheria terrae'' is a recently discovered Gram-negative bacterium. ''E. terrae'' is a temporary name for the organism, as it was only discovered in 2014 and is still undergoing scientific study. It was found to produce a previously unknown ...
''
References
External links
BURDEN of Resistance and Disease in European Nations€”An EU project to estimate the financial burden of antibiotic resistance in European hospitals
Cosmetics DatabaseHCMV drug resistance mutations tool- An informative article on multidrug resistance
MDRIpred: A web server for predicting inhibitors against drug tolerant M. Tuberculosis, published i
Chemistry Central JournalCancerDR Cancer Drug Resistance Database.
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