GENETIC MECHANISM OF DRUG RESISTANCE
GENETIC MECHANISM OF DRUG RESISTANCE
Three genetic elements are responsible for acquired antibiotic resistance each chromosomes, plasmids and transposons.
Antibiotic resistance is the most common cause of treatment failure in bacteria infectious diseases. Antibiotic resistance is classified as intrinsic resistance and acquired resistance. Intrinsic (innate) resistance suggests that the inherent properties of the bacteria are responsible for preventing antibiotic action. There are many antibiotics active against Gram-positive bacteria (absence of outer membrane) which have no effect on Gram-negative bacteria and vice versa.
Resistance to different antibiotics can arise as a consequence of mutations to chromosomal genes. Mutation can occur due to single base pair changes. Transitions involve the substitution of one purine (A or G) for another and one pyrimidine (C or T) for another. Transversions involve a change from a pyrimidine to a purine and vice versa. Frame shift mutations occur when one or two bases are inserted into the DNA sequence. More extensive changes in the DNA sequence can also occur. Deletions result in the loss of part of the DNA sequence. Insertions add extra base pairs of a gene. Transversions occur when a segment of the DNA is reversed and duplications occur when a segment of the DNA is repeated, A mutation of dihydropteroate synthetase in Streptococcus pneumoniae produces an altered enzyme with reduced affinity for sulphonamides. Chromosomal mutations in Escherichia coli result in overproduction of dihydrofolate reductase. Hence, higher concentrations of trimethoprim are required to inhibit nucleotide metabolism. Bacterial chromosome contains all the genes necessary for the growth and replication of cells. Many bacteria also possess additional circular elements of DNA which are capable of replicating and transferring of chromosomes. These extrachromosomal genetic elements are known as plasmids and can code for a number of properties including antibiotic resistance.
Plasmids have the ability to transfer within and between bacterial species. This property makes a plasmid acquired resistance much more threatening than chromosomal mutation in terms of the spread of antibiotic resistance. Plasmid transfer normally occurs by conjugation, transduction or transformation. Conjugation requires cell-to-cell contact and involves the transfer of DNA from a donor cell to a recipient cell. Plasmids which can mediate their own transfer are termed conjugative plasmids. Some plasmids which do not posses this property can be transferred if they coexist with a conjugative plasmid (mobilizable plasmids). Gram- positive and Gram-negative bacteria have the ability to conjugate and transfer the plasmids.
Transduction is a process whereby DNA is transferred by bacteriophages and plays an Staphylococcus aureus, Streptococcus pyogenes.: Certain micro-organisms have the ability to gonorrhoeae have the ability to recognize DNA from their own species and those acquired important from the environment.
Plasmids also harbour transposons, which enhances their ability to transfer antibiotic resistance genes. Transposons are mobile genetic elements capable of transferring or transposing independently from one DNA molecule to another. The DNA molecules may be chromosomes or plasmids. Plasmid or transposon-encoded chloramphenicol acetyl- transferases are responsible for resistance by inactivating the antibiotic. Chloramphenicol acetyltransferases convert chloramphenicol to an acetoxy derviative which fails to bind to acquire naked DNA from the environment by the process of transformation. Neisseria the ribosomal target.