Inhibition of Nucleic Acid Synthesis

(Reed College, Portland, Ore.). Inhibition of growth, synthesis, and permeability in Neurospora crassa by phenethyl alcohol. J. Bacteriol. 90: 29–37. 1965.—Inhibition of the growth of Neurospora crassa in still culture was detected at 0.05% and was complete at a level of 0.2% phenethyl alcohol (PEA). Benzyl alcohol was less inhibitory, and 3-phenyl-1-propanol and phenol were more inhibitory, than PEA; benzylamine and phenethylamine were less inhibitory than the analogous hydroxylated compounds. Inhibition by PEA was not reversed by synthetic mixtures of purines and pyrimidines or vitamins, or by casein digests, yeast extract, or nutrient broth. The germination of conidia was inhibited by PEA, but after an exposure of 8.5 hr no loss of viability was observed. The addition of PEA to growing shake cultures caused a simultaneous inhibition of growth and of the syntheses of ribonucleic and deoxyribonucleic acids and protein; the relationships of these compounds to mycelial dry weight and to one another were constant in growing mycelia, and PEA did not significantly affect these relationships. PEA partially inhibited the uptake of glucose, but severely restricted the accumulation of -leucine, -tryptophan, or α-aminoisobutyric acid in germinated conidia. The efflux of α-aminoisobutyric acid from germinated conidia was somewhat enhanced by PEA, but this effect was not so pronounced as the (complete) inhibition of α-aminoisobutyric acid accumulation by PEA. It is suggested that PEA affects primarily the initial influx of α-aminoisobutyric acid rather than the subsequent retention of α-aminoisobutyric acid.

Protein synthesis inhibitor - Wikipedia

Inhibitors of DNA/RNA Synthesis: ..

Inhibition of Nucleic Acid Synthesis by Antibiotics

Antimicrobial peptides: Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs) are small peptides (30-60 s) and can be isolated from all living organisms. They are essential components of the innate immune system and possess antimicrobial and immunomodulatory properties (; ). These can directly kill broad range of microbes including bacteria, fungus and viruses (). Till date more than 700 antimicrobial peptides have been identified. After identification, some of these peptides are synthesized and tested for their antimicrobial and immunomodualtory functions. Studies have been conducted on fowlicidin 1 and 3 peptides (; ). These antimicrobial peptides interact with surface membrane of bacteria either by forming discrete pores or by disrupting the membrane bilayer, leading to loss of membrane function, resulting in cell leakage and, consequently, cell death (; ; ). In relation to the full length peptide fowl-1(6-26), an analog from which five-amino terminal residues have been omitted, has helped in maintaining the antibacterial potency against a wide range of Gram-negative as well as Gram-positive bacteria that include strains which are resistant to antibiotic (). Recently, other modes of action like inhibition of the synthesis of , proteins, cell-wall components and essential enzymatic activities have also been proposed (). AMPs can be obtained from natural sources, chemical synthesis or by recombinant technology (). Some of the antimicrobial peptides such as colicin and cecropin, particularly cecropin A (1-11)-D (12-37)-Asn (CADN), act as growth promoter in poultry and have been suggested as possible alternate to antibiotic growth promoters ().

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Organic acids: In recent years, the use of acidifiers has been increased many fold and are found to have the ability to reduce many pathogenic and spoilage organisms by lowering the gut pH. Because of the development and emergence of antibiotic resistant microbes (), the utilization of s has been increased as growth promoters in animal agriculture, which could help in providing protection from adverse human health implications. In poultry diets, the use of s elicits a positive response in performance of broiler growth. In order to inhibit growth of bacteria of intestine (those which compete with host for the nutrients that are available) there is requirement of dietary acidification thereby causing reduced possibility of availability of bacterial metabolites which are toxic in nature. In the ceaca as well as small intestine it has been suggested by a number of studies that s affect the bacterial concentration. In the crop of the poultry birds they are bactericidal for (; ; ). In the young ones, acid production in the gut is insufficient and acidifiers are sometimes used in feeds to compensate it. The use of s such as formic, lactic, propionic, citric, sorbic and phosphoric acids optimizes the balance of the microflora of the gastrointestinal tract (; ; ; ; ). They lower the pH, at which the activity of proteases and beneficial bacteria is optimized and proliferation of is minimized by a direct antibacterial effect destroying their cell membranes (; ; ). In experimental studies, s have been found suitable growth promoters in pigs (; ; ) and poultry (). Supplementation of organic acid also increases intestinal colonization of spp. in chicks (). They are widely used to inhibit pathogens like salmonellae and in their undissociated forms are able to pass through their cell membrane. Inside the bacterial cell, the acid dissociates to produce H+ ions, which lower the pH causing the organism to use its energy in trying to restore the normal balance. It also disrupts DNA and protein synthesis and thus the bacteria are unable to replicate or its replication slows down. Lower pH conditions thus protect the bird from infection especially at young ages. In addition to direct microbial action, recent studies have shown that salt form of s including butyrate, propionate and acetate have shown their ability in reducing colonization in chicken cecum by enhancing innate immune defense via increased synthesis of host defense peptides (, ). Furthermore, s also reduce the contamination of litter with the harmful microorganisms, neutralize ammonia production and diminish the risk of re-infection. The effectiveness of organic acids in poultry may also depend on the composition of the diet and its buffering capacity. The combination of citric, lactic, formic and orthophosphoric acid at doses of 2-8 kg ton-1 of feed are found effective. Propionic acid suppresses the growth of moulds and prevents the formation of mycotoxins. Short-chain s such as butyrate are considered potential alternatives to antibiotic growth promoters. Butyric acid at 0.2% level of incorporation can help to maintain the performance and carcass quality of broilers (). The Medium-chain Fatty Acids (MCFA), caproic, caprylic and capric acid, are also capable of inhibiting the growth of at low concentrations . The ifiers are thus considered effective and recognized as safe, with no concern over getting into human food chain.

Rifampicin blocks initiation of RNA synthesis by specifically inhibiting bacterial RNA polymerase.
the majority of antibiotics that block bacterial protein synthesis interfere with ..

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The reduction in growth of the bacterial strains is very closely associated with changes in cell morphology in the various bacterial strains. Both the transformed and non transformed DH5α strains form long filamentous structures after addition of caffeine to growing cultures. The length of these filamentous forms was noted to increase with further incubation in the caffeine supplemented medium. Although there are reports on formation of long filamentous structure upon exposure to caffeine for various strains of (SundarRaj and Dhala, 1965) till to date there are no reports on the effect of caffeine on morphology of and other bacterial strains. However, previous reports show that subjected to stress factor such as nutrient depletion forms long filaments instead of separating into individual daughter cells (Koch, 2005). Filamentous form of has been also reported in case of exposure of the bacteria to chromate (Ackerley ., 2006). Perhaps the same mechanism is adopted by to overcome the effect of caffeine on growing culture. Complete or partial lysis of the cells is noted in case of other Gram negative bacterial speciesunder study. Similarly cell lysis was noted in the case of Gram positive bacterium, after caffeine addition. This might be due to inhibition of important cellular functions such as protein synthesis or DNA metabolism by caffeine. In contrast, no noticeable change in morphology or lysis was observed in other Gram positive bacterium after addition of caffeine. These results clearly showed that coccus form is more resistant to caffeine than bacilli form.

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Caffeine when added at log phase of growth retards the growth of , , , andwithin a very short time, but the growth of sp. was enhanced upon addition of caffeine. This is because of the utilization of caffeine as a source of nutrient by the caffeine degrading strain and consequent conversion of caffeine to non toxic intermediates. Previous studies on have shown that caffeine inhibits synthesis of DNA (Sandlie ., 1980) and impairs RNA and protein synthesis. This can be the reason for non viability of cells upon caffeine exposure and lysis in case of other bacterial species.

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1. In living cells there are hundreds of different enzymes working together in a coordinated manner, and since cells neither synthesize nor break down more material than is required for normal metabolism and growth, precise enzyme regulation is required for turning metabolic reactions on and off.
2. There is tremendous diversity in the mechanisms bacteria use to regulate enzyme synthesis and enzyme activity.
3. Ways in which enzymes can be controlled or regulated iinclude controlling the synthesis of the enzyme (genetic control) and controlling the activity of the enzyme (feedback inhibition).
4. In prokaryotes, genetic control of enzyme activity includes the induction or repression of enzyme synthesis by regulatory proteins that can bind to DNA and either block or enhance the function of RNA polymerase, the enzyme required for transcription.
5. An operon is a set of genes collectively controlled by a regulatory protein.
6. Regulatory proteins may function either as repressors or activators.
7. Repressors are regulatory proteins that block transcription of mRNA by preventing RNA polymerase from transcribing the coding sequence for the enzymes.
8. Some repressors, as in the case of the trp operon, are synthesized in a form that cannot by itself bind to the operator. This is referred to as a repressible system. The binding of a molecule called a corepressor, however, alters the shape of the regulatory protein to a form that can bind to the operator and subsequently block transcription.
9. Some repressors, as in the case of the lac operon, are synthesized in a form that readily binds to the operator and blocks transcription. However, the binding of a molecule called an inducer alters the shape of the regulatory protein in a way that now blocks its binding to the operator and thus permits transcription. This is referred to as an inducible system.
10. Activators are regulatory proteins that promote transcription of mRNA by enabling RNA polymerase to transcribing the coding sequence for the enzymes.
11. Enhancers are regulatory proteins that bind to DNA located some distance from the operon they control by working with DNA-bending proteins. The DNA-bending proteins bend the DNA in a way that now allows the enhancer to interact with the promoter in such a way that RNA polymerase can now bind and initiate transcription
12. Bacteria also use translational control of enzyme synthesis. One method is for the bacteria to produce noncoding RNA (ncRNA) molecules that are complementary to the mRNA coding for the enzyme, and when the small RNA binds to the mRNA by complementary base pairing, ribosomes cannot attach to the mRNA, the mRNA is not transcribed and translated into protein, and the enzyme is not made. In bacteria, these ncRNAs are often called small RNAs (sRNAs).
13. Feedback inhibition controls the activity of the enzyme rather than its synthesis and can be noncompetitive or competitive.
14. In the case of non-competitive inhibition, the inhibitor is the end product of a metabolic pathway that is able to bind the allosteric site on the enzyme. Binding of the inhibitor to the allosteric site alters the shape of the enzyme's active site thus preventing binding of the first substrate in the metabolic pathway. In this way, the pathway is turned off.
15. In the case of what is called competitive inhibition, the inhibitor is the end product of an enzymatic reaction. That end product is also capable of reacting with the enzyme's active site and prevents the enzyme from binding its normal substrate. As a result, the end product is no longer synthesized.