drug resistance

Drug, toxin, or chemical resistance is a consequence of evolution 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 impossible in the entire target population, resistance to the drug will inevitably follow. This can be seen in cancerous tumors where some cells may develop resistance to the drugs used in chemotherapy.{{cite web|url=http://www.merckmanuals.com/home/drugs/factors_affecting_response_to_drugs/tolerance_and_resistance_to_drugs.html|title=Tolerance and Resistance to Drugs|work=Merck Manuals Consumer Version}} Chemotherapy causes fibroblasts near tumors to produce large amounts of the protein WNT16B. This protein stimulates the growth of cancer cells which are drug-resistant.[https://www.bbc.co.uk/news/health-19111700 "Chemo 'Undermines Itself' Through Rogue Response"],BBC News, 5 August 2012. MicroRNAs have also been shown to affect acquired drug resistance in cancer cells and this can be used for therapeutic purposes.{{cite journal | vauthors = Ghasabi M, Mansoori B, Mohammadi A, Duijf PH, Shomali N, Shirafkan N, Mokhtarzadeh A, Baradaran B | title = MicroRNAs in cancer drug resistance: Basic evidence and clinical applications | journal = Journal of Cellular Physiology | volume = x | issue = 3 | pages = 2152–2168 | pmid = 30146724 | doi = 10.1002/jcp.26810 | year = 2019 | s2cid = 52092652 }} Malaria in 2012 has become a resurgent threat in South East Asia and sub-Saharan Africa, and drug-resistant strains of Plasmodium falciparum are posing massive problems for health authorities.{{cite news|url=https://www.bbc.co.uk/news/health-17628172|title=Resistance spread 'compromising' fight against malaria|newspaper=BBC News|date=2012-04-05|last1=McGrath|first1=Matt}}{{cite web|url=https://www.bbc.com/news/science-environment-34583854|title=Drug-resistant malaria can infect African mosquitoes|last=Morelle|first=Rebecca | author-link=Rebecca Morelle | name-list-style = vanc |date=20 October 2015|work=BBC News|access-date=21 October 2015}} Leprosy has shown an increasing resistance to dapsone.

A rapid process of sharing resistance exists among single-celled organisms, and is termed horizontal gene transfer in which there is a direct exchange of genes, particularly in the biofilm state.{{cite journal | vauthors = Molin S, Tolker-Nielsen T | title = Gene transfer occurs with enhanced efficiency in biofilms and induces enhanced stabilisation of the biofilm structure | journal = Current Opinion in Biotechnology | volume = 14 | issue = 3 | pages = 255–61 | date = June 2003 | pmid = 12849777 | doi = 10.1016/S0958-1669(03)00036-3 }} A similar asexual method is used by fungi and is called "parasexuality". Examples of drug-resistant strains are to be found in microorganisms{{cite web|url=http://www.tulane.edu/~wiser/protozoology/notes/drugs.html|title=Mechanisms of drug action and resistance|work=tulane.edu}} such as bacteria and viruses, parasites both endo- and ecto-, plants, fungi, arthropods,{{cite journal | vauthors = Brun LO, Wilson JT, Daynes P | title = Ethion resistance in the cattle tick (Boophilus microplus) in New Caledonia. | journal = International Journal of Pest Management | date = March 1983 | volume = 29 | issue = 1 | pages = 16–22 | url = http://horizon.documentation.ird.fr/exl-doc/pleins_textes/pleins_textes_5/b_fdi_12-13/15697.pdf | doi=10.1080/09670878309370763}}{{cite web|url=http://potatobeetle.org/AJPR_Review.html|title=Review Article on Colorado Potato Beetle Resistance to Insecticides|website=potatobeetle.org|access-date=1 October 2018}} mammals,{{cite journal | vauthors = Lund M | title = Rodent resistance to the anticoagulant rodenticides, with particular reference to Denmark | journal = Bulletin of the World Health Organization | volume = 47 | issue = 5 | pages = 611–8 | year = 1972 | pmid = 4540680 | pmc = 2480843 }} birds,{{cite journal | vauthors = Shefte N, Bruggers RL, Schafer EW | title = Repellency and toxicity of three bird control chemicals to four species of African grain-eating birds.| journal = The Journal of Wildlife Management | date = April 1982 | volume = 46 | issue = 2 | pages = 453–7 | jstor=3808656 | doi = 10.2307/3808656 }} reptiles,{{cite web|url=http://www.reptilechannel.com/reptile-news/snake/garter-snakes-and-toxic-newts.aspx|title=Reptiles Magazine, your source for reptile and herp care, breeding, and enthusiast articles|work=reptilechannel.com|url-status=dead|archive-url=https://web.archive.org/web/20110103121634/http://www.reptilechannel.com/reptile-news/snake/garter-snakes-and-toxic-newts.aspx|archive-date=2011-01-03}} fish, and amphibians.

In the domestic environment, drug-resistant strains of organism may arise from seemingly safe activities such as the use of bleach,{{cite web|url=http://www.physorg.com/news145799281.html|title=How household bleach works to kill bacteria|work=physorg.com}} tooth-brushing and mouthwashing,{{cite web |url=http://www.healthstores.com/dentists/new_dental_products.htm |title=Compete50 The complete mouth care products |access-date=2010-07-18 |url-status=dead |archive-url=https://web.archive.org/web/20100403082807/http://www.healthstores.com/dentists/new_dental_products.htm |archive-date=2010-04-03 }} the use of antibiotics, disinfectants and detergents, shampoos, and soaps, particularly antibacterial soaps,{{cite news |title=The Dirt on Clean: Antibacterial Soap v Regular Soap |url=http://www.cbc.ca/marketplace/webextras/triclosan/antibacterial.html?triclosan |url-status=dead |archive-url=https://web.archive.org/web/20110806152152/http://www.cbc.ca/marketplace/webextras/triclosan/antibacterial.html |archive-date=6 August 2011 |work=CBC News }}{{cite web|url=http://health.howstuffworks.com/skin-care/cleansing/myths/antibacterial-soap-outlawed.htm|title=Should antibacterial soap be outlawed?|work=HowStuffWorks|date=2007-11-07}} hand-washing,{{cite journal | vauthors = Weber DJ, Rutala WA | s2cid = 20734025 | title = Use of germicides in the home and the healthcare setting: is there a relationship between germicide use and antibiotic resistance? | journal = Infection Control and Hospital Epidemiology | volume = 27 | issue = 10 | pages = 1107–19 | date = October 2006 | pmid = 17006819 | doi = 10.1086/507964 }} surface sprays, application of deodorants, sunblocks and any cosmetic or health-care product, insecticides, and dips.{{cite journal | vauthors = Yoon KS, Kwon DH, Strycharz JP, Hollingsworth CS, Lee SH, Clark JM | title = Biochemical and molecular analysis of deltamethrin resistance in the common bed bug (Hemiptera: Cimicidae) | journal = Journal of Medical Entomology | volume = 45 | issue = 6 | pages = 1092–101 | date = November 2008 | pmid = 19058634 | doi = 10.1603/0022-2585(2008)45[1092:BAMAOD]2.0.CO;2 | doi-broken-date = 24 December 2024 | s2cid = 27422270 }} The chemicals contained in these preparations, besides harming beneficial organisms, may intentionally or inadvertently target organisms that have the potential to develop resistance.{{cite web |url= http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Antibacterial_cleaning_products | archive-url = https://web.archive.org/web/20150304071300/http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Antibacterial_cleaning_products | archive-date = 4 March 2015 | url-status = dead |title=Antibacterial cleaning products | publisher = Australian Department of Health & Human Services |access-date=1 October 2018}}

The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are:{{cite journal | vauthors = Li XZ, Nikaido H | title = Efflux-mediated drug resistance in bacteria: an update | journal = Drugs | volume = 69 | issue = 12 | pages = 1555–623 | date = August 2009 | pmid = 19678712 | pmc = 2847397 | doi = 10.2165/11317030-000000000-00000 }}{{cite journal | vauthors = Sandhu P, Akhter Y | title = Evolution of structural fitness and multifunctional aspects of mycobacterial RND family transporters | journal = Archives of Microbiology | volume = 200 | issue = 1 | pages = 19–31 | date = January 2018 | pmid = 28951954 | doi = 10.1007/s00203-017-1434-6 | bibcode = 2018ArMic.200...19S | s2cid = 13656026 }}

1. Drug inactivation or modification: e.g., enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of β-lactamases.
2. Alteration of target site: e.g., alteration of PBP — the binding target site of penicillins — in MRSA and other penicillin-resistant bacteria.
3. Alteration of metabolic pathway: e.g., some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides. Instead, like mammalian cells, they turn to utilizing preformed folic acid.
4. Reduced drug accumulation: by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface.

{{Cite book|title=Introduction to Microbiology second edition|last=Catherine A. Ingraham|first=John L. Ingraham|year=2000}}

{{Cite book|title=Introduction to Microbiology|url=https://archive.org/details/introductiontomi0000ingr|url-access=registration|last=Catherine A. Ingraham|first=John L. Ingraham|year=2000}}

Biological cost is a measure of the increased energy metabolism required to achieve a function.{{cite journal | vauthors = Gillespie SH, McHugh TD | title = The biological cost of antimicrobial resistance | journal = Trends Microbiol | volume = 5 | issue = 9 | pages = 337–9 | date = September 1997 | pmid = 9294886 | doi = 10.1016/S0966-842X(97)01101-3 }}

Drug resistance has a high metabolic price in pathogens for which this concept is relevant (bacteria,{{cite journal | vauthors = Wichelhaus TA, Böddinghaus B, Besier S, Schäfer V, Brade V, Ludwig A | title = Biological cost of rifampin resistance from the perspective of Staphylococcus aureus | journal = Antimicrobial Agents and Chemotherapy | volume = 46 | issue = 11 | pages = 3381–5 | date = November 2002 | pmid = 12384339 | pmc = 128759 | doi = 10.1128/AAC.46.11.3381-3385.2002 }} 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.{{Cite journal|last1=Händel|first1=Nadine|last2=Schuurmans|first2=J. Merijn|last3=Brul|first3=Stanley|last4=ter Kuile|first4=Benno H.|date=August 2013|title=Compensation of the Metabolic Costs of Antibiotic Resistance by Physiological Adaptation in Escherichia coli|journal=Antimicrobial Agents and Chemotherapy|volume=57|issue=8|pages=3752–3762|doi=10.1128/AAC.02096-12|issn=0066-4804|pmc=3719774|pmid=23716056}} 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.{{cn|date=June 2022}}

In humans, the gene ABCB1 encodes MDR1(p-glycoprotein) which is a key transporter of medications on the cellular level. If MDR1 is overexpressed, drug resistance increases.{{cite journal | vauthors = Ramos-Peñafiel C, Olarte-Carrillo I, Cerón-Maldonado R, Rozen-Fuller E, Kassack-Ipiña JJ, Meléndez-Mier G, Collazo-Jaloma J, Martínez-Tovar A | title = Effect of metformin on the survival of patients with ALL who express high levels of the ABCB1 drug resistance gene | language = En | journal = Journal of Translational Medicine | volume = 16 | issue = 1 | pages = 245 | date = September 2018 | pmid = 30176891 | pmc = 6122769 | doi = 10.1186/s12967-018-1620-6 | doi-access = free }} 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, 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 antibiotics (such as penicillin and cephalosporins) can be circumvented by using antibiotics such as nafcillin that are not susceptible to destruction by certain beta-lactamases (the group of enzymes responsible for breaking down beta-lactams).{{cite journal | vauthors = Barber M, Waterworth PM | journal = British Medical Journal | volume = 2 | issue = 5405 | pages = 344–9 | date = August 1964 | pmid = 14160224 | pmc = 1816326 | doi = 10.1136/bmj.2.5405.344 | title = Penicillinase-resistant Penicillins and Cephalosporins }} Beta-lactam bacterial resistance can also be dealt with by administering beta-lactam antibiotics with drugs that block beta-lactamases such as clavulanic acid so that the antibiotics can work without getting destroyed by the bacteria first.{{cite journal | vauthors = Bush K | title = Beta-lactamase inhibitors from laboratory to clinic | journal = Clinical Microbiology Reviews | volume = 1 | issue = 1 | pages = 109–23 | date = January 1988 | pmid = 3060240 | pmc = 358033 | doi = 10.1128/CMR.1.1.109 }} Researchers have recognized the need for new drugs that inhibit bacterial efflux pumps, which cause resistance to multiple antibiotics such as beta-lactams, quinolones, chloramphenicol, and trimethoprim by sending molecules of those antibiotics out of the bacterial cell.{{cite journal | vauthors = Webber MA, Piddock LJ | title = The importance of efflux pumps in bacterial antibiotic resistance | journal = The Journal of Antimicrobial Chemotherapy | volume = 51 | issue = 1 | pages = 9–11 | date = January 2003 | pmid = 12493781 | doi = 10.1093/jac/dkg050 | doi-access = free }}{{cite journal | vauthors = Tegos GP, Haynes M, Strouse JJ, Khan MM, Bologa CG, Oprea TI, Sklar LA | title = Microbial efflux pump inhibition: tactics and strategies | journal = Current Pharmaceutical Design | volume = 17 | issue = 13 | pages = 1291–302 | date = 2011 | pmid = 21470111 | pmc = 3717411 | doi = 10.2174/138161211795703726 }} 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.{{cite journal | vauthors = Glew RH, Millering RS, Wennersten C | title = Comparative synergistic activity of nafcillin, oxacillin, and methicillin in combination with gentamicin against | journal = Antimicrobial Agents and Chemotherapy | volume = 7 | issue = 6 | pages = 828–32 | date = June 1975 | pmid = 1155924 | pmc = 429234 | doi = 10.1128/aac.7.6.828 }}

Destruction of the resistant bacteria can also be achieved by phage therapy, in which a specific bacteriophage (virus that kills bacteria) is used.{{Cite journal|last1=Lin|first1=Derek M|last2=Koskella|first2=Britt|last3=Lin|first3=Henry C|date=2017|title=Phage therapy: An alternative to antibiotics in the age of multi-drug resistance|journal=World Journal of Gastrointestinal Pharmacology and Therapeutics|language=en|volume=8|issue=3|pages=162–173|doi=10.4292/wjgpt.v8.i3.162|issn=2150-5349|pmc=5547374|pmid=28828194 |doi-access=free }}

• Antibiotic resistance
• Fecal bacteriotherapy
• Mass drug administration
• Multidrug resistance
• Pharmacoepidemiology
• Physical factors affecting microbial life
• Small multidrug resistance protein
• Eleftheria terrae

{{reflist}}

• [https://archive.today/20070701212012/http://www.eu-burden.info/burden/pages/home.php BURDEN of Resistance and Disease in European Nations]—An EU project to estimate the financial burden of antibiotic resistance in European hospitals
• [http://www.merckmanuals.com/home/drugs/factors_affecting_response_to_drugs/tolerance_and_resistance_to_drugs.html Merck - Tolerance and Resistance]
• [https://web.archive.org/web/20130512032005/https://www.cosmeticsdatabase.com/ Cosmetics Database]
• [http://www.informatik.uni-ulm.de/ni/staff/HKestler/hcmv HCMV drug resistance mutations tool]
• [https://web.archive.org/web/20111109151918/http://www.pharmaceutical-int.com/article/combating-drug-resistance.html Combating Drug Resistance] - An informative article on multidrug resistance
• [https://www.fda.gov/drugs/resourcesforyou/consumers/ucm143568.htm Battle of the Bugs: Fighting Antibiotic Resistance]
• [http://crdd.osdd.net/oscadd/mdri/ MDRIpred] : A web server for predicting inhibitors against drug tolerant M. Tuberculosis, published in [https://web.archive.org/web/20140714114112/http://journal.chemistrycentral.com/content/7/1/49/abstract Chemistry Central Journal]
• [http://crdd.osdd.net/raghava/cancerdr/ CancerDR]: Cancer Drug Resistance Database. [http://www.nature.com/srep/2013/130313/srep01445/full/srep01445.html Scientific Reports 3, 1445]

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Category:Immunology

Category:Psychopharmacology