Drug resistance

File:WhatIsDrugResistance.gif

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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite web Template:Verify source</ref> 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.<ref>Template:Cite web Template:Verify source</ref><ref>Template:Cite journal Template:Verify source</ref>

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.<ref>Template:Cite book Template:Verify source</ref>

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.<ref>Template:Cite book Template:Verify source</ref> Some of the best alternative sources to reduce the chance of antibiotic resistance are probiotics, prebiotics, dietary fibers, enzymes, organic acids, phytogenics.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and P aeruginosa were the six main causes (73%) of AMR-associated mortality in 2019, according to the 2022 Global Burden of Disease research.<ref>Template:Cite journal</ref>

AMR not only causes death and disability, but it also has high financial expenses. AMR may lead to US$ 1 trillion in higher healthcare expenses by 2050 and US$ 1 trillion to US$ 3.4 trillion in annual GDP losses by 2030, according to World Bank estimations. <ref>Template:Cite web</ref>

Types

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.<ref>Template:Cite web</ref> 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.<ref>"Chemo 'Undermines Itself' Through Rogue Response",BBC News, 5 August 2012.</ref> MicroRNAs have also been shown to affect acquired drug resistance in cancer cells and this can be used for therapeutic purposes.<ref name="Ghasabi2018">Template:Cite journal</ref> 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.<ref>Template:Cite news</ref><ref>Template:Cite web</ref> 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.<ref>Template:Cite journal</ref> A similar asexual method is used by fungi and is called "parasexuality". Examples of drug-resistant strains are to be found in microorganisms<ref>Template:Cite web</ref> such as bacteria and viruses, parasites both endo- and ecto-, plants, fungi, arthropods,<ref>Template:Cite journal</ref><ref>Template:Cite web</ref> mammals,<ref>Template:Cite journal</ref> birds,<ref>Template:Cite journal</ref> reptiles,<ref name="Reptile Channel">Template:Cite web</ref> fish, and amphibians.<ref name="Reptile Channel"/>

In the domestic environment, drug-resistant strains of organism may arise from seemingly safe activities such as the use of bleach,<ref>Template:Cite web</ref> tooth-brushing and mouthwashing,<ref>Template:Cite web</ref> the use of antibiotics, disinfectants and detergents, shampoos, and soaps, particularly antibacterial soaps,<ref>Template:Cite news</ref><ref>Template:Cite web</ref> hand-washing,<ref>Template:Cite journal</ref> surface sprays, application of deodorants, sunblocks and any cosmetic or health-care product, insecticides, and dips.<ref>Template:Cite journal</ref> The chemicals contained in these preparations, besides harming beneficial organisms, may intentionally or inadvertently target organisms that have the potential to develop resistance.<ref>Template:Cite web</ref>

Mechanisms

The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are:<ref name= "pmid19678712">Template:Cite journal</ref><ref>Template:Cite journal</ref>

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

<ref>Template:Cite book</ref> <ref name="Catherine A. Ingraham 2000">Template:Cite book</ref>

Mechanism	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

Biological cost is a measure of the increased energy metabolism required to achieve a function.<ref name="pmid9294886">Template:Cite journal</ref>

Drug resistance has a high metabolic price in pathogens<ref name="pmid9294886"/> for which this concept is relevant (bacteria,<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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.Template:Cn

Treatment

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.<ref name=":0">Template:Cite journal</ref> Therefore, ABCB1 levels can be monitored.<ref name=":0" /> 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.<ref name=":0" />

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).<ref name=PRP>Template:Cite journal</ref> 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.<ref name=Bush>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

Destruction of the resistant bacteria can also be achieved by phage therapy, in which a specific bacteriophage (virus that kills bacteria) is used.<ref>Template:Cite journal</ref>

See also

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

External links

• 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
• Cosmetics Database
• HCMV drug resistance mutations tool
• Combating Drug Resistance - An informative article on multidrug resistance
• Battle of the Bugs: Fighting Antibiotic Resistance
• MDRIpred : A web server for predicting inhibitors against drug tolerant M. Tuberculosis, published in Chemistry Central Journal
• CancerDR: Cancer Drug Resistance Database. Scientific Reports 3, 1445