DNA Synthesis Inhibitors

DNA synthesis inhibitors
Nucleic acid inhibitors are chemicals which inhibit the production of nucleic acids including both DNA and RNA. DNA and RNA inhibitors inhibit enzyme action in DNA replication in the same way as the topoisomerase inhibitors we discussed earlier.
Topoisomerase inhibitors (1) (10) are chemicals which interfere with the enzymes that allow DNA strands to separate and to re-join, a process that is required for the division of bacteria and without which DNA cannot effectively replicate. DNA helicase is the enzyme which allows the hydrogen bonds between strands to separate and DNA polymerase is the enzyme allowing nucleic acids to form bonds and it is these enzymes and some others that are inhibited by these chemicals. This
means that the bacteria will cease to multiply and the immune system will be able to digest the pathogens. Enzymes are biological catalysts that lower the activation energy of a reaction to increase rate. The inhibition of the topoisomerase enzyme means that the condensation reaction which forms the phosphodiester bonds between the phosphate group and the deoxyribose sugar of adjacent nucleic acid molecules cannot occur. These chemicals may also cause decatenation (7), the process by which links in a chain are broken, in this case the bonds between the sugar and phosphate groups of adjacent nucleic acids in the DNA strand are broken.
Another mechanism of antibiotic action is the inhibition of metabolic reactions by competitive inhibition or by erroneous incorporation.
Competitive inhibitors are molecules with a similar shape to the substrate which bind to the active site of the enzyme preventing the enzyme substrate complex from forming. For example, the antibiotic sulanilamide combines with the enzyme which is supposed to convert a chemical called para-aminobenzenoic acid into folic acid preventing the reaction that is useful to the bacterium. Inhibiting the formation of folic acid prevents the bacteria from growing as folic acid (12) is very important to many of the essential processes of the cell. Erroneous incorporation is the process by which molecules with very similar shape and structure to the nucleotides that form DNA and as a result may be incorporated into the DNA molecule. However because these do not form complementary base pairs with free nucleotides neither DNA replication nor transcription (the formation of RNA molecules from DNA) can
occur.
Resistance mechanisms
Inherent resistance is the existing natural resistance of bacteria due to existing variation caused by random mutation. This can be due to the bacteria lacking a target protein or molecule meaning the antibiotic cannot bind to the bacteria. It can also be due to the absence of a transport system making the bacteria impermeable to the antibiotic.
Inactivation of the drug can occur by several mechanisms.
This can occur due to the production of a chemical which alters the structure of the antibiotic (1), e.g. and enzyme that breaks down part of an antibiotic molecule. Alteration of the structure of the antibiotic target can also be the cause of the inactivation of an antibiotic. This change in structure means the antibiotic molecule can no longer bind to the bacteria and so cannot carry out its role. An alteration in structure can also occur in enzymes causing change to the shape of their active site. This means that an antibiotic that worked by competitive inhibition or erroneous incorporation would no longer have a complementary shape and so would be unable to bind to or inhibit the enzyme. It is also possible that a change to the pathway of a reaction or an increase in its rate would counteract or overwhelm the action of the
inhibitor.
Impacts
The impacts on human health are clear as there is an increased risk of long term health issues and even mortality (5) if the bacterium is resistant to most or all antibiotics. The economic impacts include the cost to society which is projected to be $100 trillion globally by 2050. These costs, for example, include extended stays in hospital not only exacerbating the strain on NHS beds and resources but also preventing the patient from attending work. This will contribute to the already daunting problems the NHS is facing. Social impacts will also be significant at a projected 10 million additional deaths per year which will have a severe effect. There are also emotional impacts associated with recovering from serious infections.
To actually fight these resistant strains doctors are having to employ older antibiotics which have less pervasive resistance or to combine antibiotics into a single treatment. This means introducing the bacteria to the final resort antibiotics which may cause resistance to develop even in these. Without effective antibiotics to combat infections mortality would increase.
As the issue escalates with a growing number of cases and of new antibiotic resistant strains of bacteria the cost will only increase economically and socially.