Mechanism of Action of Antibiotics that Inhibit DNA Function, Replication and Transcription

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Antibacterial antibiotics are commonly classified based on their mechanism of action, chemical structure, or spectrum of activity. Most target bacterial functions or growth processes. Those that target the bacterial cell wall (penicillins and cephalosporins) or the cell membrane (polymyxins), or interfere with essential bacterial enzymes (rifamycins, lipiarmycins, quinolones, and sulfonamides) have bactericidal activities. Those that target protein synthesis (macrolides, lincosamides and tetracyclines) are usually bacteriostatic (with the exception of bactericidal aminoglycosides). Further categorization is based on their target specificity. "Narrow-spectrum" antibacterial antibiotics target specific types of bacteria, such as Gram-negative or Gram-positive bacteria, whereas broad-spectrum antibiotics affect a wide range of bacteria.

 Four new classes of antibacterial antibiotics have been brought into clinical use: cyclic lipopeptides (such as daptomycin), glycylcyclines (such as tigecycline), oxazolidinones (such as linezolid), and lipiarmycins (such as fidaxomicin).

Mechanism of Action of Antibiotics that Inhibit DNA Function, Replication and Transcription

 

This category of antibiotics that interfere with nucleic acid polymerization can be divided into two main classes: (1) those that perturb the template function of DNA; (2) those that inhibit the enzymes associated with DNA replication and transcription.

The former class can be divided into those that chemically modify DNA and those that form complexes with DNA. One example of those that chemically modify DNA is the mitomycins. They bind covalently and irreversibly to DNA and show very little selectivity. Thus, they are very toxic and are not used as antibiotics. The bleomycins are a group of less toxic antibiotics that act by producing multiple breaks in both single and double-stranded DNA. However, they are used only against certain types of tumors. Two final examples of antibiotics that chemically modify DNA are the imidazole derivatives (i.e. metronidazole) and the nitrofurans (i.e. nitrofurantoin). Metronidazole is 90-100% effective against sexually transmitted urogenital infections caused by Trichomonas vaginalis. Nitrofurantoin is used in the treatment of urinary tract infections. Both antibiotics act by inducing breakage in DNA strands via direct chemical interaction. Specifically, the nitro group of the antibiotic is converted to a nitronate radical in the cell. The radical form of the antibiotic is the activated form that actually attacks and breaks DNA strands. One example of the antibiotics that form complexes with DNA—also known as intercalators—is actinomycin D. However, like the mitomycins, they are highly toxic and of limited use. Two other examples are daunorubicin and doxorubicin that are among the most effective anti-tumor antibiotics. They indirectly cause via intercalation multiple breaks in the DNA strand.

As mentioned above, there are also antibiotics that act by inhibiting enzymes associated with DNA replication and transcription. Examples of those that inhibit DNA replication include the quinolones, coumermycins and novobiocin. The quinolones selectively inhibit DNA gyrase (aka topoisomerase II) by binding to the A subunit of the enzyme at exposed single strand ends of the cut DNA chain. Hence, DNA gyrase becomes unable to reseal the DNA with the end result that the chromosome becomes highly fragmented. Quinolones include nalidixic acid and oxolinic acid, but the newer second-generation quinonlones—the 4-fluoroquinolones (i.e. norfloxacin and ciprofloxacin)—are much more effective. The coumermycins and novobiocin also inhibit DNA gyrase but by binding to the ATP site on the B subunit. It is useful to note that there is no cross resistance between these two types of antibiotics that affect DNA replication. In addition, to date, no specific inhibitor of bacterial DNA polymerases has been reported.

Examples of those antibiotics that inhibit DNA transcription include the rifamycins streptolidigin and lipiarmycin. Some common characteristics of these antibiotics is that they are very selective against RNA polymerase, they do not directly affect DNA synthesis and they are bacteriostatic unless the complex formed with the enzyme is virtually irreversible. Lipiarmycin is a true inhibitor of RNA synthesis initiation whereas the exact mechanism of action of the rifamycins is debatable. According to one source they act by inhibiting the initiation stage of transcription in which the first nucleotide is incorporated into the mRNA. According to another they act by inhibiting formation of the second phosphodiester bond of mRNA and thus the elongation of it. What is known with certainty is that the rifamycins form a virtually irreversible complex with the beta subunit of RNA polymerase. They are highly effective agents in treating tuberculous meningitis and staphylococci infections.

β-Lactam antibiotics (beta-lactam antibiotics) are a broad class of antibiotics, consisting of all antibiotic agents that contains a β-lactam ring in their molecular structures. This includes penicillin derivatives (penams), cephalosporins (cephems),monobactams, and carbapenems. Most β-lactam antibiotics work by inhibiting wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics.

Bacteria often develop resistance to β-lactam antibiotics by synthesizing a β-lactamase, an enzyme that attacks the β-lactam ring. To overcome this resistance, β-lactam antibiotics are often given with β-lactamase inhibitors such as clavulanic acid

β-Lactam antibiotics are bacteriocidal, and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms, being the outermost and primary component of the wall.

β-Lactam antibiotics block not only the division of bacteria, including cyanobacteria, but also the division of cyanelles, the photosynthetic organelles of the glaucophytes, and the division of chloroplasts of bryophytes. In contrast, they have no effect on the plastids of the highly developed vascular plants. This is supporting the endosymbiotic theory and indicates an evolution of plastid division in land plants. Under normal circumstances, peptidoglycan precursors signal a reorganisation of the bacterial cell wall and, as a consequence, trigger the activation of autolytic cell wall hydrolases. Inhibition of cross-linkage by β-lactams causes a build-up of peptidoglycan precursors, which triggers the digestion of existing peptidoglycan by autolytic hydrolases without the production of new peptidoglycan. As a result, the bactericidal action of β-lactam antibiotics is further enhanced.

bacteriophage is a virus that infects and replicates within a bacterium. The term is derived from 'bacteria' and the Greek “to devour". Bacteriophages are composed of proteins that encapsulate a DNA or RNA genome, and may have relatively simple or elaborate structures. Their genomes may encode as few as four genes, and as many as hundreds of genes. Phages replicate within the bacterium following the injection of their genome into its cytoplasm. Bacteriophages are among the most common and diverse entities in the biosphere.

Phages are widely distributed in locations populated by bacterial hosts, such as soil or the intestines of animals. One of the densest natural sources for phages and other viruses is sea water, where up to 9×108 virions per milliliter have been found in microbial mats at the surface, and up to 70% of marine bacteria may be infected by phages.

vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as foreign, destroy it, and keep a record of it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters.

Vaccines can be prophylactic (example: to prevent or ameliorate the effects of a future infection by any natural or "wild" pathogen), or therapeutic (e.g., vaccines against cancer are also being investigated;

The terms vaccine and vaccination are derived from Variolae vaccinae (smallpox of the cow), the term devised by Edward Jenner to denote cowpox.

Types

Vaccines are dead or inactivated organisms or purified products derived from them.

There are several types of vaccines in use.These represent different strategies used to try to reduce risk of illness, while retaining the ability to induce a beneficial immune response.

Inactivated

Some vaccines contain inactivated, but previously virulent, micro-organisms that have been destroyed with chemicals, heat, radioactivity, or antibiotics. Examples are influenzacholerabubonic plaguepoliohepatitis A, and rabies.

Attenuated

Some vaccines contain live, attenuated microorganisms. Many of these are active viruses that have been cultivated under conditions that disable their virulent properties, or that use closely related but less dangerous organisms to produce a broad immune response. Although most attenuated vaccines are viral, some are bacterial in nature. Examples include the viral diseases yellow fever, measles, rubella, and mumps, and the bacterial disease typhoid. The live Mycobacterium tuberculosis vaccine developed by Calmette and Guérin is not made of a contagious strain, but contains a virulently modified strain called "BCG" used to elicit an immune response to the vaccine. The live attenuated vaccine-containing strain Yersinia pestis EV is used for plague immunization. Attenuated vaccines have some advantages and disadvantages. They typically provoke more durable immunological responses and are the preferred type for healthy adults. But they may not be safe for use in immunocompromised individuals, and may rarely mutate to a virulent form and cause disease.

Toxoid

Toxoid vaccines are made from inactivated toxic compounds that cause illness rather than the micro-organism. Examples of toxoid-based vaccines include tetanus and diphtheria. Toxoid vaccines are known for their efficacy. Not all toxoids are for micro-organisms; for example, Crotalus atrox toxoid is used to vaccinate dogs against rattlesnake bites.

Subunit

Protein subunit – rather than introducing an inactivated or attenuated micro-organism to an immune system (which would constitute a "whole-agent" vaccine), a fragment of it can create an immune response. Examples include the subunit vaccine against Hepatitis B virus that is composed of only the surface proteins of the virus (previously extracted from the blood serum of chronically infected patients, but now produced by recombination of the viral genes into yeast), the virus-like particle (VLP) vaccine against human papillomavirus (HPV) that is composed of the viral major capsid protein, and the hemagglutinin and neuraminidase subunits of theinfluenza virus. Subunit vaccine is being used for plague immunization.

Conjugate

Conjugate – certain bacteria have polysaccharide outer coats that are poorly immunogenic. By linking these outer coats to proteins (e.g., toxins), the immune system can be led to recognize the polysaccharide as if it were a protein antigen. This approach is used in the Haemophilus influenzae type B vaccine.

Vaccines do not guarantee complete protection from a disease. Sometimes, this is because the host's immune system simply does not respond adequately or at all. This may be due to a lowered immunity in general (diabetes, steroid use, HIV infection, age) or because the host's immune system does not have a B cell capable of generating antibodies to that antigen.

Even if the host develops antibodies, the human immune system is not perfect and in any case the immune system might still not be able to defeat the infection immediately. In this case, the infection will be less severe and heal faster.

Adjuvants are typically used to boost immune response. Most often, aluminium adjuvants are used, but adjuvants like squalene are also used in some vaccines, and more vaccines with squalene and phosphate adjuvants are being tested. Larger doses are used in some cases for older people (50–75 years and up), whose immune response to a given vaccine is not as strong.

The efficacy or performance of the vaccine is dependent on a number of factors:

  • the disease itself (for some diseases vaccination performs better than for other diseases)
  • the strain of vaccine (some vaccinations are for different strains of the disease)
  • whether one kept to the timetable for the vaccinations
  • some individuals are "non-responders" to certain vaccines, meaning that they do not generate antibodies even after being vaccinated correctly
  • Other factors such as ethnicity, age, or genetic predisposition.

When a vaccinated individual does develop the disease vaccinated against, the disease is likely to be milder than without vaccination.[7]

The following are important considerations in the effectiveness of a vaccination program:]

  1. careful modelling to anticipate the impact that an immunization campaign will have on the epidemiology of the disease in the medium to long term
  2. ongoing surveillance for the relevant disease following introduction of a new vaccine
  3. Maintaining high immunization rates, even when a disease has become rare.

Adverse effects

Vaccination given during childhood is generally safe. Adverse effects if any are generally mild. The rate of side effects depends on the vaccine in question. Some potential side effects include: fever, pain around the injection site, and muscle aches. Severe side effects are extremely rare.

 

Posted by: Venkata Krishna Rao. in Science | Date: 23/02/2016

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