The spread of drug-resistant pathogens is one of the most serious threats to public health.
The antimicrobial drugs are prepared and used widely but many diseases are resisting treatment due to drug resistance. Neisseria gonorrhoeae, the causative agent of gonorrhea is a common example. Gonorrhea was first treated successfully with sulfonamides in 1936, but by 1942 most strains were resistant and the drug then was penicillin. Within 16 years a penicillin-resistant strain - penicillinase-producing gonococcus emerged, and penicillin is no longer used to treat gonorrhea. Methicillin resistant S. aureus (MRSA) and Vancomycin resistant S. aureus (VRSA) strain are common now, they resist other antibiotics including ciprofloxacin, and penicillin. Vancomycin-resistant enterococci (VRE) is also very common.
There is a direct correlation between the daily use of antibiotics and the percent of resistant isolates. In 1946, almost all strains of Staphylococcus were penicillin sensitive. Today most hospital strains are resistant to penicillin G, and some also resistant to methicillin and/or gentamicin and only can be treated with Vancomycin. Some strains of Enterococcus have become resistant to most antibiotics, including Vancomycin.
Multi-resistant Mycobacterium tuberculosis also is common. (MDR-TB -TB caused by bacteria that are resistant to at least two of the first-line TB antibiotics, isoniazid and rifampin. XDR-TB - a rare type of MDR-TB that is resistant to nearly all TB drugs. XDR-TB is caused by bacteria that are resistant to isoniazid and rifampin, and any fluoroquinolone and at least one of the three second-line injectable drugs).
Thus drug resistance is an extremely serious public health problem.
Factors contributing to drug resistance
· Most serious problem arises from drug misuse such as the antibiotic prescriptions given in hospitals without clear evidence of infection or adequate medical indication. Antibacterial drugs administered to patients with colds, influenza, viral pneumonia, and other viral disease is a common example.
Frequently antibiotics are prescribed without culturing and identifying the pathogen or without determining bacterial sensitivity to the drug. Toxic, broad-spectrum antibiotics are sometimes given in place of narrow-spectrum drugs as a substitute for culture and sensitivity testing, with the consequent risk of dangerous side effects, opportunistic infections, and the selection of drug-resistant mutants.
· The situation is made worse by patients not completing their course of medication. When antibiotic treatment is ended too early, drug-resistant mutants may survive.
· Drugs are available without prescription to the public in many countries; people practicing self-administration of antibiotics further increase the prevalence of drug-resistant strains.
· The use of antibiotics in animal feeds is another contributing factor to increasing drug resistance.
The addition of low levels of antibiotics to livestock feeds raises the efficiency and rate of weight gain in cattle, pigs, and chickens (partially because of infection control in overcrowded animal populations). However, this also increases the number of drug-resistant bacteria in animal intestinal tracts.
· The spread of antibiotic resistance can be due to quite subtle factors. For example, products such as soap and deodorants often now contain triclosan and other germicides. The widespread use of triclosan favors an increase in antibiotic resistance
Drug Resistance
Bacteria often become resistant in several different ways. Resistant mutants arise spontaneously and are then selected for in the presence of the drug.
A particular type of resistance mechanism is not confined to a single class of drugs.
Two bacteria may use different resistance mechanisms to withstand the same chemotherapeutic agent.
Bacteria can resist the action of antibiotics by
(1) preventing access to the target of the antibiotic
(2) altering target of the antibiotic
(3) degrading the antibiotic
(4) rapid expulsion of the antibiotic.
(5) alteration of susceptible enzymes
(6) alternate pathway to bypass the sequence inhibited
1. Preventing access to (or altering) the target of the antibiotic
Pathogens often become resistant simply by preventing entrance of the drug.
- Many gram-negative bacteria have an outer membrane which cannot be penetrated by penicillin G and hence are unaffected by it.
- A decrease in permeability can lead to sulfonamide resistance.
- Mycobacteria resist many drugs because of the high content of mycolic acids in a complex lipid layer outside their peptidoglycan. This layer is impermeable to most water soluble drugs.
- Genetic mutations that lead to changes in penicillin binding proteins also make a cell resistant.
2, Altering the target of the antibiotic
Antibiotics acts on a specific target. Resistance arises when the target enzyme or cellular structure is modified so that it is no longer susceptible to the drug. This drastically reduces antibiotic binding.
- . The affinity of ribosomes for erythromycin and chloramphenicol can be decreased by a change in the 23S rRNA to which they bind.
- . Enterococci become resistant to Vancomycin by changing the terminal D-alanine-D-alanine in their peptidoglycan to a D-alanine-D-lactate.
3. Expulsion/exclusion of Drugs
Another resistance strategy is to pump the drug out of the cell after it has entered. Some pathogens have plasma membrane translocases, often called efflux pumps that expel drugs. They are relatively nonspecific and can pump many different drugs. So, these transport proteins are called multidrug resistance pumps. Many are drug/proton antiporters—that is, protons enter the cell as the drug leaves. Such systems are present in E. coli, P. aeruginosa, and S. aureus.
4. Inactivation of drugs through enzyme hydrolysis
Many bacterial pathogens resist attack by inactivating drugs using enzymatic hydrolysis. The hydrolysis of the β-lactam ring of penicillins by the enzyme penicillinase is a classical example.
5. Inactivation of drugs through chemical modification
Drugs are inactivated by the addition of chemical groups.
- Chloramphenicol contains two hydroxyl groups that can be acetylated by the enzyme chloramphenicol acyltransferase with acetyl CoA as the donor.
- Aminoglycosides can be modified and inactivated in several ways. Acetyltransferases catalyze the acetylation of amino groups. Some aminoglycoside modifying enzymes catalyze the addition of either phosphates (phosphotransferases) or adenyl groups (adenyltransferases) to hydroxyl groups.
6. Alteration of susceptible enzymes
Antimetabolite action may be resisted through alteration of susceptible enzymes. In sulfonamide resistant bacteria, the enzyme-(dihydropteroic acid synthetase) that uses p-aminobenzoic acid during folic acid synthesis often has a much lower affinity for sulfonamides.
Resistant bacteria may either use an alternate pathway to bypass the sequence inhibited by the agent or increase the production of the target metabolite. For example, some bacteria are resistant to sulfonamides simply because they use preformed folic acid from their surroundings rather than synthesize it themselves. Other strains increase their rate of folic acid production and thus counteract sulfonamide inhibition.
The Origin and Transmission of Drug Resistance
Genes for drug resistance may be present on bacterial chromosomes, plasmids, transposons, and integrons. Because they are often found on mobile genetic elements (plasmids, transposons, and integrons), they can freely exchange between bacteria.
Spontaneous mutations in the bacterial chromosome, (although not very often) can make bacteria drug resistant. Usually such mutations result in a change in the drug target; therefore the antibiotic cannot bind and inhibit growth (e.g., the protein target to which streptomycin binds on bacterial ribosomes).
Many mutants are probably destroyed by natural host resistance mechanisms. However, when a patient is being treated extensively with antibiotics, some resistant mutants may survive and flourish because of their competitive advantage over nonresistant strains.
Frequently a bacterial pathogen is drug resistant because it has a plasmid bearing one or more resistance genes; such plasmids are called R plasmids (resistance plasmids).
Plasmid resistance genes often code for enzymes that destroy or modify drugs; for example, the hydrolysis of penicillin or the acetylation of chloramphenicol and aminoglycoside drugs. Plasmid associated genes have been implicated in resistance to the aminoglycosides, choramphenicol, penicillins and cephalosporins, erythromycin, tetracyclines, sulfonamides, and others.
Once a bacterial cell possesses an R plasmid, the plasmid (or its genes) may be transferred to other cells quite rapidly through normal gene exchange processes such as conjugation, transduction, and transformation.
Because a single plasmid may carry genes for resistance to several drugs, a pathogen population can become resistant to several antibiotics simultaneously, even though the infected patient is being treated with only one drug.
Antibiotic resistance genes can be located on genetic elements other than plasmids such as
1) composite transposons which bear more than one resistance gene. eg., Tn5 (kanamycin, bleomycin, streptomycin), Tn9 (chloramphenicol), Tn10 (tetracycline), Tn21 (streptomycin, spectinomycin, sulfonamide), Tn551 (erythromycin), and Tn4001 (gentamicin, tobramycin, kanamycin). Resistance genes on composite transposons can move rapidly between plasmids and through a bacterial population.
2) Several resistance genes are carried together as gene cassettes in association with a genetic element known as an integron. An integron is composed of an integrase gene and sequences for site-specific recombination. Thus integrons also are important in spreading resistance genes.
3) Conjugative transposons, like composite transposons, can carry resistance genes. Because they are capable of moving between bacteria by conjugation, they are also effective in spreading resistance.
Strategies to reduce the emergence of drug resistance.
The drug can be given in a high enough concentration to destroy susceptible bacteria and most spontaneous mutants that might arise during treatment.
Sometimes two or even three different drugs can be administered simultaneously with the hope that each drug will prevent the emergence of resistance to the other. This approach is used in treating tuberculosis and malaria.
Finally, chemotherapeutic drugs, particularly broad-spectrum drugs, should be used only when definitely necessary. If possible, the pathogen should be identified, drug sensitivity tests run, and the proper narrow-spectrum drug employed.
But, despite efforts to control the emergence and spread of drug resistance, the situation continues to worsen. Antibiotics should be used in ways that reduce the development of resistance. Another approach is to search for new antibiotics that microorganisms have never encountered. Structure-based or rational drug design is a third option.
Developing “enhancers”, which are cationic peptides that disrupt bacterial membranes by displacing their magnesium ions which help antibiotics to penetrate and rapidly exert their effects, is another approach.
Development of efflux-pump inhibitors to be given along with antibiotics to prevent their expulsion by the resistant pathogen is also useful.
New antibiotics are developed that are effective against drug-resistant pathogens.
Information that is coming from the sequencing and analysis of pathogen genomes is also useful in identifying new targets for antimicrobial drugs.
Felix d’Herelle, one of the discoverers of bacterial viruses or bacteriophages, proposed that bacteriophages could be used to treat bacterial diseases. Currently Russian physicians use bacteriophages to treat many bacterial infections. American companies are actively conducting research on phage therapy and preparing to carry out clinical trials.
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