Drug resistance

This article is about pathogen resistance to the effects of drugs. For human resistance to the effects of drugs, see Drug tolerance.

An illustrative diagram explaining drug resistance.

Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition.[1] The term is used in the context of resistance that pathogens or cancers have "acquired", that is, resistance has evolved. Antimicrobial resistance and antineoplastic resistance 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.[2] Furthermore, there is mounting concern over the abuse of antibiotics in the farming of livestock, which in the European Union alone accounts for three times the volume dispensed to humans – leading to development of super-resistant bacteria.[3][4]

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, vancomycin-resistant enterococci and macrolide-resistant Streptococcus, while examples of antibiotic-modifying microbes are Pseudomonas aeruginosa and aminoglycoside-resistant Acinetobacter baumannii.[5]

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.[6] Some of the best alternative sources to reduce the chance of antibiotic resistance are probiotics, prebiotics, dietary fibers, enzymes, organic acids, phytogenics.[7][8]

## Contents

* 1 Types
* 2 Mechanisms
* 2.1 Mechanisms of Acquired Drug Resistance
* 3 Metabolic cost
* 4 Treatment
* 5 See also
* 6 References
* 7 External links

## Types[edit | edit source]

In 2022, WHO launched a strategy to respond to urgent problem of antimalarial drug resistance in Africa[9]

Diagram that shows how gene transfer facilitates the spread of 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.[10]

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.[11]

MicroRNAs have also been shown to affect acquired drug resistance in cancer cells and this can be used for therapeutic purposes.[12]

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.[13][14] 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.[15]

A similar asexual method is used by fungi and is called "parasexuality". Examples of drug-resistant strains are to be found in microorganisms[16] such as bacteria and viruses, parasites both endo- and ecto-, plants, fungi, arthropods,[17][18] mammals,[19] birds,[20] reptiles,[21] fish, and amphibians.[21]

In the domestic environment, drug-resistant strains of organism may arise from seemingly safe activities such as the use of bleach,[22] tooth-brushing and mouthwashing,[23] the use of antibiotics, disinfectants and detergents, shampoos, and soaps, particularly antibacterial soaps,[24][25] hand-washing,[26] surface sprays, application of deodorants, sunblocks and any cosmetic or health-care product, insecticides, and dips.[27] The chemicals contained in these preparations, besides harming beneficial organisms, may intentionally or inadvertently target organisms that have the potential to develop resistance.[28]

## Mechanisms[edit | edit source]

Scanning electron micrograph of methicillin-resistant Staphylococcus aureus( bacteria shown is strain MRSA252, a leading cause of hospital-associated infections in the U.S. and U.K.)

The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are:[29][30]

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.

### Mechanisms of Acquired Drug Resistance[edit | edit source]

Mechanism [31] | Antimicrobial Agent  | Drug Action  | Mechanism of Resistance

|
|
|

Destroy drug  | Aminoglycoside

Beta-lactam antibiotics (penicillin and cephalosporin)

Chloramphenicol

| Binds to 30S Ribosome subunit, inhibiting protein synthesis

Binds to penicillin-binding proteins, Inhibiting peptidoglycan synthesis

Bind to 50S ribosome subunit, inhibiting formation of peptide bonds

| Plasmid encode enzymes that chemically alter the drug (e.g., by acetylation or phosphorylation), thereby inactivating it.

Plasmid encode beta-lactamase, which open the beta-lactam ring, inactivating it.

Plasmid encode an enzyme that acetylate the drug, thereby inactivating it.

Alters drug target  | Aminoglycosides

Beta-lactam antibiotics (penicillin and cephalosporin)

Erythromycin

Quinolones

Rifampin

Trimethoprim

| Binds to 30S Ribosome subunit, inhibiting protein synthesis

Binds to penicillin-binding proteins, Inhibiting peptidoglycan synthesis

Bind to 50S ribosome subunit, inhibiting protein synthesis

Binds to DNA topoisomerase, an enzyme essential for DNA synthesis

Binds to the RNA polymerase; inhibiting initiation of RNA synthesis

Inhibit the enzyme dihydrofolate reduces, blocking the folic acid pathway

| Bacteria make an altered 30S ribosomes that does not bind to the drug.

Bacteria make an altered penicillin-binding proteins, that do not bind to the drug.

Bacteria make a form of 50S ribosome that does not binds to the drug.

Bacteria make an altered DNA topoisomerase that does not binds to the drug.

Bacteria make an altered polymerase that does not binds to the drug.

Bacteria make an altered enzyme that does not binds to the drug.

Inhibits drug entry or removes drug  | Penicillin

Erythromycin

Tetracycline

| Binds to penicillin-binding proteins, Inhibiting peptidoglycan synthesis

Bind to 50S ribosome subunit, inhibiting protein synthesis

Binds to 30S Ribosome subunit, inhibiting protein synthesis by blocking tRNA

| Bacteria change shape of the outer membrane porin proteins, preventing drug from entering cell.

New membrane transport system prevent drug from entering cell.

New membrane transport system pumps drug out of cell.

## Metabolic cost[edit | edit source]

Biological cost is a measure of the increased energy metabolism required to achieve a function.

Drug resistance has a high metabolic price[32] in pathogens for which this concept is relevant (bacteria,[33] 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.[34] 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.[citation needed]

## Treatment[edit | edit source]

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.[35] Therefore, ABCB1 levels can be monitored.[35] 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.[35]

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).[36] 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.[37] Recently, 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.[38][39] 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.[40]

Destruction of the resistant bacteria can also be achieved by phage therapy, in which a specific bacteriophage (virus that kills bacteria) is used.[41]

## See also[edit | edit source]

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

## References[edit | edit source]

1. ↑ Alfarouk, KO; Stock, CM; Taylor, S; Walsh, M; Muddathir, AK; Verduzco, D; Bashir, AH; Mohammed, OY; Elhassan, GO; Harguindey, S; Reshkin, SJ; Ibrahim, ME; Rauch, C (2015). "Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp". Cancer Cell International. 15: 71. doi:10.1186/s12935-015-0221-1. PMC 4502609. PMID 26180516.
2. ↑ "Antibiotic Resistance and Evolution". detectingdesign.com. Archived from the original on 2017-07-02. Retrieved 2022-09-28.[verification needed]
3. ↑ Harvey, Fiona (16 October 2016). "Use of strongest antibiotics rises to record levels on European farms". the Guardian. Archived from the original on 1 October 2018. Retrieved 1 October 2018.[verification needed]
4. ↑ Duckenfield, Joan (2011-12-30). "Antibiotic Resistance Due to Modern Agricultural Practices: An Ethical Perspective". Journal of Agricultural and Environmental Ethics. 26 (2): 333–350. doi:10.1007/s10806-011-9370-y. ISSN 1187-7863. S2CID 55736918.[verification needed]
5. ↑ Fisher, Jed F.; Mobashery, Shahriar (2010). "Enzymology of Bacterial Resistance". Comprehensive Natural Products II. Volume 8: Enzymes and Enzyme Mechanisms. Elsevier. pp. 443–201. doi:10.1016/B978-008045382-8.00161-1. ISBN 978-0-08-045382-8.[verification needed]
6. ↑ Institute of Medicine (US) Forum on Emerging Infections; Knobler, S. L.; Lemon, S. M.; Najafi, M.; Burroughs, T. (2003). Reading: The Resistance Phenomenon in Microbes and Infectious Disease Vectors: Implications for Human Health and Strategies for Containment -- Workshop Summary - The National Academies Press. nap.edu. doi:10.17226/10651. ISBN 978-0-309-08854-1. PMID 22649806. Archived from the original on 2015-01-12. Retrieved 2022-09-28.[verification needed]
7. ↑ Jha, Rajesh; Das, Razib; Oak, Sophia; Mishra, Pravin (2020). "Probiotics (Direct-Fed Microbials) in Poultry Nutrition and Their Effects on Nutrient Utilization, Growth and Laying Performance, and Gut Health: A Systematic Review". Animals. 10 (10): 1863. doi:10.3390/ani10101863. PMC 7602066. PMID 33066185.
8. ↑ Jha, Rajesh; Mishra, Pravin (2021-04-19). "Dietary fiber in poultry nutrition and their effects on nutrient utilization, performance, gut health, and on the environment: a review". Journal of Animal Science and Biotechnology. 12 (1): 51. doi:10.1186/s40104-021-00576-0. ISSN 2049-1891. PMC 8054369. PMID 33866972. Archived from the original on 2023-03-26. Retrieved 2022-09-28.
9. ↑ "Fact sheet about malaria". www.who.int. Archived from the original on 2020-05-02. Retrieved 2024-05-31.
10. ↑ "Tolerance and Resistance to Drugs". Merck Manuals Consumer Version. Archived from the original on 2015-03-26. Retrieved 2022-09-28.
11. ↑ "Chemo 'Undermines Itself' Through Rogue Response" Archived 2022-11-29 at the Wayback Machine,BBC News, 5 August 2012.
12. ↑ Ghasabi M, Mansoori B, Mohammadi A, Duijf PH, Shomali N, Shirafkan N, Mokhtarzadeh A, Baradaran B (2019). "MicroRNAs in cancer drug resistance: Basic evidence and clinical applications". Journal of Cellular Physiology. x (3): 2152–2168. doi:10.1002/jcp.26810. PMID 30146724. S2CID 52092652.
13. ↑ McGrath, Matt (2012-04-05). "Resistance spread 'compromising' fight against malaria". BBC News. Archived from the original on 2022-12-25. Retrieved 2022-09-28.
14. ↑ Morelle R (20 October 2015). "Drug-resistant malaria can infect African mosquitoes". BBC News. Archived from the original on 21 October 2015. Retrieved 21 October 2015.
15. ↑ Molin S, Tolker-Nielsen T (June 2003). "Gene transfer occurs with enhanced efficiency in biofilms and induces enhanced stabilisation of the biofilm structure". Current Opinion in Biotechnology. 14 (3): 255–61. doi:10.1016/S0958-1669(03)00036-3. PMID 12849777.
16. ↑ "Mechanisms of drug action and resistance". tulane.edu. Archived from the original on 2022-10-01. Retrieved 2022-09-28.
17. ↑ Brun LO, Wilson JT, Daynes P (March 1983). "Ethion resistance in the cattle tick (Boophilus microplus) in New Caledonia" (PDF). International Journal of Pest Management. 29 (1): 16–22. doi:10.1080/09670878309370763. Archived (PDF) from the original on 2022-11-29. Retrieved 2022-09-28.
18. ↑ "Review Article on Colorado Potato Beetle Resistance to Insecticides". potatobeetle.org. Archived from the original on 2 October 2018. Retrieved 1 October 2018.
19. ↑ Lund M (1972). "Rodent resistance to the anticoagulant rodenticides, with particular reference to Denmark". Bulletin of the World Health Organization. 47 (5): 611–8. PMC 2480843. PMID 4540680.
20. ↑ Shefte N, Bruggers RL, Schafer EW (April 1982). "Repellency and toxicity of three bird control chemicals to four species of African grain-eating birds". The Journal of Wildlife Management. 46 (2): 453–7. doi:10.2307/3808656. JSTOR 3808656.
21. ↑ 21.0 21.1 "Reptiles Magazine, your source for reptile and herp care, breeding, and enthusiast articles". reptilechannel.com. Archived from the original on 2011-01-03.
22. ↑ "How household bleach works to kill bacteria". physorg.com. Archived from the original on 2023-03-26. Retrieved 2022-09-28.
23. ↑ "Compete50 The complete mouth care products". Archived from the original on 2010-04-03. Retrieved 2010-07-18.
24. ↑ "The Dirt on Clean: Antibacterial Soap v Regular Soap". CBC News. Archived from the original on 6 August 2011.
25. ↑ "Should antibacterial soap be outlawed?". HowStuffWorks. 2007-11-07. Archived from the original on 2022-09-30. Retrieved 2022-09-28.
26. ↑ Weber DJ, Rutala WA (October 2006). "Use of germicides in the home and the healthcare setting: is there a relationship between germicide use and antibiotic resistance?". Infection Control and Hospital Epidemiology. 27 (10): 1107–19. doi:10.1086/507964. PMID 17006819. S2CID 20734025.
27. ↑ Yoon KS, Kwon DH, Strycharz JP, Hollingsworth CS, Lee SH, Clark JM (November 2008). "Biochemical and molecular analysis of deltamethrin resistance in the common bed bug (Hemiptera: Cimicidae)". Journal of Medical Entomology. 45 (6): 1092–101. doi:10.1603/0022-2585(2008)45[1092:BAMAOD]2.0.CO;2. PMID 19058634. S2CID 27422270.
28. ↑ "Antibacterial cleaning products". Australian Department of Health & Human Services. Archived from the original on 4 March 2015. Retrieved 1 October 2018.
29. ↑ Li XZ, Nikaido H (August 2009). "Efflux-mediated drug resistance in bacteria: an update". Drugs. 69 (12): 1555–623. doi:10.2165/11317030-000000000-00000. PMC 2847397. PMID 19678712.
30. ↑ Sandhu P, Akhter Y (January 2018). "Evolution of structural fitness and multifunctional aspects of mycobacterial RND family transporters". Archives of Microbiology. 200 (1): 19–31. doi:10.1007/s00203-017-1434-6. PMID 28951954. S2CID 13656026.
31. ↑ Catherine A. Ingraham, John L. Ingraham (2000). Introduction to Microbiology.
32. ↑ Gillespie SH, McHugh TD (September 1997). "The biological cost of antimicrobial resistance". Trends in Microbiology. 5 (9): 337–9. doi:10.1016/S0966-842X(97)01101-3. PMID 9294886.
33. ↑ Wichelhaus TA, Böddinghaus B, Besier S, Schäfer V, Brade V, Ludwig A (November 2002). "Biological cost of rifampin resistance from the perspective of Staphylococcus aureus". Antimicrobial Agents and Chemotherapy. 46 (11): 3381–5. doi:10.1128/AAC.46.11.3381-3385.2002. PMC 128759. PMID 12384339.
34. ↑ Händel, Nadine; Schuurmans, J. Merijn; Brul, Stanley; ter Kuile, Benno H. (August 2013). "Compensation of the Metabolic Costs of Antibiotic Resistance by Physiological Adaptation in Escherichia coli". Antimicrobial Agents and Chemotherapy. 57 (8): 3752–3762. doi:10.1128/AAC.02096-12. ISSN 0066-4804. PMC 3719774. PMID 23716056.
35. ↑ 35.0 35.1 35.2 Ramos-Peñafiel C, Olarte-Carrillo I, Cerón-Maldonado R, Rozen-Fuller E, Kassack-Ipiña JJ, Meléndez-Mier G, Collazo-Jaloma J, Martínez-Tovar A (September 2018). "Effect of metformin on the survival of patients with ALL who express high levels of the ABCB1 drug resistance gene". Journal of Translational Medicine. 16 (1): 245. doi:10.1186/s12967-018-1620-6. PMC 6122769. PMID 30176891.
36. ↑ Barber M, Waterworth PM (August 1964). "Penicillinase-resistant Penicillins and Cephalosporins". British Medical Journal. 2 (5405): 344–9. doi:10.1136/bmj.2.5405.344. PMC 1816326. PMID 14160224.
37. ↑ Bush K (January 1988). "Beta-lactamase inhibitors from laboratory to clinic". Clinical Microbiology Reviews. 1 (1): 109–23. doi:10.1128/CMR.1.1.109. PMC 358033. PMID 3060240.
38. ↑ Webber MA, Piddock LJ (January 2003). "The importance of efflux pumps in bacterial antibiotic resistance". The Journal of Antimicrobial Chemotherapy. 51 (1): 9–11. doi:10.1093/jac/dkg050. PMID 12493781.
39. ↑ Tegos GP, Haynes M, Strouse JJ, Khan MM, Bologa CG, Oprea TI, Sklar LA (2011). "Microbial efflux pump inhibition: tactics and strategies". Current Pharmaceutical Design. 17 (13): 1291–302. doi:10.2174/138161211795703726. PMC 3717411. PMID 21470111.
40. ↑ Glew RH, Millering RS, Wennersten C (June 1975). "Comparative synergistic activity of nafcillin, oxacillin, and methicillin in combination with gentamicin against". Antimicrobial Agents and Chemotherapy. 7 (6): 828–32. doi:10.1128/aac.7.6.828. PMC 429234. PMID 1155924.
41. ↑ Lin, Derek M; Koskella, Britt; Lin, Henry C (2017). "Phage therapy: An alternative to antibiotics in the age of multi-drug resistance". World Journal of Gastrointestinal Pharmacology and Therapeutics. 8 (3): 162–173. doi:10.4292/wjgpt.v8.i3.162. ISSN 2150-5349. PMC 5547374. PMID 28828194.

## External links[edit | edit source]

* BURDEN of Resistance and Disease in European Nations—An EU project to estimate the financial burden of antibiotic resistance in European hospitals
* Merck - Tolerance and Resistance Archived 2015-03-26 at the Wayback Machine
* Cosmetics Database
* HCMV drug resistance mutations tool Archived 2018-04-22 at the Wayback Machine
* Combating Drug Resistance \- An informative article on multidrug resistance
* Battle of the Bugs: Fighting Antibiotic Resistance Archived 2019-04-23 at the Wayback Machine
* MDRIpred Archived 2014-01-05 at the Wayback Machine : A web server for predicting inhibitors against drug tolerant M. Tuberculosis, published in Chemistry Central Journal
* CancerDR Archived 2013-06-27 at the Wayback Machine: Cancer Drug Resistance Database. Scientific Reports 3, 1445 Archived 2015-08-05 at the Wayback Machine

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