Drug Resistance:

The most serious threat to the successful treatment of microbial diseases is the spread of drug-resistant pathogens. There are different ways in which bacteria develop resistant to drugs. 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 drug and resistant mutants arise spontaneously and the mutants are not created directly by exposure to a drug. One mechanism of gaining resistance by pathogens is by preventing entrance of the drug. Penicillin G is ineffective towards gram negative bacteria as it cannot penetrate the envelopes outer membrane. Mycobacteria resist drugs because of the high content of mycolic acids in a complex lipid layer outside their peptdidoglycan which is just impermeable to most drugs. A decrease in permeability can lead to sulfonamide resistance too. The second mechanism of resistance is to pump the drugs out of the cell after it has entered. Translocases present on the plasma membrane of pathogens, often called efflux pumps expel the drugs. These are also called as multidrug resistance pumps as these are relatively nonspecific and can pump many different drugs. Many are drug/proton anitporters – where a proton enters the cell and the drug leaves (E. coli, Pseudomonas aeroginosa, Mycobacterium smegmatis and staphylococcus aureus). The third mechanism is to inactivate the drugs through chemical modifications. Best known example is the hydrolysis of the β-lactam ring of much penicillin by the enzyme penicillinase. Sometimes, groups can also be added to the drugs in order to inactivate them. For example, chloramphenicol contains two hydroxyl groups that can be acetylated in a reaction catalyzed by the enzyme chloramphenicol acyltransferase with acetyl CoA as the donor, which catalyze the acetylating of amino groups.

Basically, the chemotherapeutic agent's acts on a specific target and when the target enzyme or organelle is modified, resistance arises as it is no longer susceptible to the drug. For example, erythromycin and chloramphenicol have the affinity towards the ribosomes and this can be decreased by a change in the 23S rRNA to which they bind. The antibiotic binding can also be reduced as in the case of Enterococci, which become resistant to vancomycin by changing the terminal D-alanine-D-alanine in their peptidoglycan to D-alanine-D-lactate. In sulfonamide resistant bacteria the enzyme that uses p-aminobenzoinc acid during folic acid synthesis often has a much lower affinity for sulfonamides. Mycobacterium tuberculosis has become resistant to the drug rifampin due mutations that alter the β subunit of its RNA polymerase and the drug cannot bind to it and block the initiation of transcription.

Origin and transmission of drug resistance:

Bacterial chromosomes and plasmids harbour the genes for drug resistance. Spontaneous mutations in the bacterial chromosome, although they do not occur very often, will make bacteria drug resistant. These mutations, sometimes results in a change in the drug receptor; therefore the antibiotic cannot bind and inhibit .Host resistance mechanisms help in destroying the mutants, however, when a patient is being treated extensively with antibiotics, some resistant mutants may survive and flourish. 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). These genes often code for enzymes that destroy or modify drugs; for example, the hydrolysis of penicillin or the acetylation of chloramphenicol as discussed in the previous section and many others. These R plasmids can also be rapidly transferred from one bacterial cell which possesses it to another through normal gene exchange processes such as conjugation, transduction and transformation. A single plasmid may contain resistance genes for several drugs, and hence a pathogen population can become resistant to several antibiotics simultaneously.

Antibiotic resistance genes are also located on genetic elements other than plasmids. Many composite transposons contain genes for antibiotic resistance both in gram-negative as well as gram-positive bacteria. Few examples and their resistance markers are Tn 5 (kanamucin, bleomycin, streptomycin), Tn 9 (Chloramphenicol), Tn 10 (tetracycline), Tn 21 (Streptomycin, spectinomycin, sulfonamide), Tn 551 (erthyromycin) and Tn 4001 (gentamicin, tobramycin, kanamycin). These genes on composite transposons can move rapidly between plasmids and through a bacterial population very rapidly.

Extensive drug treatment can also lead to the development and spread of antibiotic-resistant strains because the antibiotic destroys normal, susceptible bacteria that would usually compete with drug-resistant pathogens leading to a super infection. This is a significant problem because of the existence of multiple-drug resistant bacteria.

In order to discourage the emergence of drug resistance, several strategies can be employed like; the drug can be given in a high enough concentration to destroy susceptible bacteria and most spontaneous mutants that might arise during treatment. Two different drugs can be administered sometimes, with a hope that each drug will prevent the emergence of resistance to the other. Finally, broad-spectrum drugs, should be used only when definitely necessary. Another approach is to search for new antibiotics that microorganism have never encountered. Structure based or rational drug design is a third option. Pharmaceutical companies are now looking for drugs to treat diseases like AIDS, cancer and the common cold by using the bioinformatics tools. Sequencing and analysis of pathogen genomes almost certainly will be useful in identifying new targets for antimicrobial drugs. In recent times, bacteriophages are being used to treat many bacterial infections also called Phage therapy. Bandages are saturated with phage solutions, phage mixtures are administered with orally, and phage preparations are given intravenously to treat Staphylococcus infections.