Antibacterial Drugs

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Uneconomic Species

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ability to control the adverse activities of a wide variety of that group of bacteria

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Pathogenic bacterium infect mammals by

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1.Penetration of the epithelial surface by the pathogen; 2.Interference with, or evasion of the defense mechanisms of the host; 3.Multiplication in the environment of the host’s tissue; 4.Damage to the host’s tissues, some of which is caused by the decompartmentalization of the cells themselves, and some by the host’s own immune system.

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Basis of selectivity

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1.The target that is inhibited is found only in the bacterium so that the host remains unaffected – often referred to as comparative biochemistry. 2.The antibiotic is concentrated within the bacterial cell but not the host cell – comparative selectivity. 3.The target is the bacterial cell wall, a structure that does not exist in eukaryotes – comparative cytology.

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Gram-positive Bacteria

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Retains an iodine-crystal violet stain when treated with an organic solvent, usually alcohol or acetone.
Gram-positive bacteria are highly acidic (teichoic acid) and bind the dyestuff.

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Gram-Negative Bacteria

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The outer membrane is similar in structure to the cytoplasmic membrane except that the outer leaflet does not contain any phospholipid molecules.

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Amphiphilic Polyene Antibiotics

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treat fungal infections of the blood and which selectively binds to ergosterol

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Azole group Antifungal

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Mainly for topical infections. Their mechanism of action is the inhibition of the fungal enzyme lanosterol 14-alpha- demethylase which is necessary to convert lanosterol to ergosterol.

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Tolnaftate

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Inhibits the enzyme squalene epoxidase that is essential for the synthesis of ergosterol.

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Sulfonamides and Diaminopyrimidines

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The sulfonamides are structural analogs of p-aminobenzoic acid and bind much more strongly to bacterial dihydrofolate reductase, which produce tetrahydrofolic acid, which is crucial in providing one-carbon units in the synthesis of purines and pyrimidines.

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Rifamycin

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Blocks the initial DNA/RNA-polymerase complex. Blocks the path of the incipient RNA chain. Prevents the formation of the first phosphodiester bond.

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Floxacin

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Inhibits gyrase (topoisomerise II) which unwinds positively supercoiled DNA by intermittently breaks a phosphodiester bond in one of the strands of the double helix, then introducing a negative supercoil and finally resealing the break so that the DNA is intact for transcription. Is active against both Gram-positive and Gram-negative bacteria

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Streptomycin

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Binds irreversibly to the 30S of the initiation complex distorting the A site, so that the fMet-tRNA is released. Binding to the ribosome during synthesis slows the process and leads to misreading of the mRNA codons. The main action springs from the irreversible block of protein synthesis mediated at the initiation phase.

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Gentamycin, neomycin, kanamycin, amikacin, and tobramycin

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bactericidal and bind to the 30S mostly. They do not bind to the site selected by streptomycin. They inhibit the binding of factor EF-G, which is involved in translocation.

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Macrolides

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Bacteriostatic and displays selectivity by to the 50S. Premature ejection of peptidyl-tRNA suring translocation.

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Tetracyclines

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Bacteriostatic and inhibits protein synthesis at 70S. Inhibits the binding of aminoacyl-tRNA to the ribosomal acceptor A-site by disruption of the codon-anticodon interaction between mRNA and tRNA.

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Chloramphenicol

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Broad-spectrum. Inhibits the peptidyl transferase reaction, apparently by binding directly to the 23S rRNA strand of the 50S subunit. Causes a lethal blood anemia.

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Oxazolidinone

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Principally against Gram-positive organisms. Inhibits by binding to the 50S ribosomal subunit at the initiation step, thus terminating the growth of the peptide chain. The binding takes place similar to Chloramphenicol, but not at the same location.

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D-cycloserine

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An analogue of D-alanine and is a Stage 1 inhibitor. It blocks glycan synthesis by competitive inhibition of both alanine racemase and D-alanyl-D-alanine synthase

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Bacitracin

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Stage 2 inhibitor and binds to the membrane-bound pyrophosphate form of the lipid carrier molecule after the disaccharidepentapeptide unit has been transferred to the growing peptidoglycan chain. It prevents dephosphorylation of the pyrophosphate which is necessary to initiate another round of chain extension. It is important to note that it blocks the substrate and not the enzyme!

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Glycopeptide antibiotics
(Vancomycin) Stage 3

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Binds through hydrogen bonding to the acetyl-D-alanyl-D-alanine portion of the muramic acid pentapeptide pyrophosphate-undecaprenol precursor so that the coupling trans-glycosylation step cannot occur. Thus extension of the polymer is terminated. Once again by binding to a substrate rather than an enzyme.

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Beta-lactam Antibiotics
Stage 3

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Inhibits the transpeptidation reaction by binding to the transpeptidase enzyme which accomplishes the crosslinking step. The reason for the high specificity of these antibiotics is that their core structure strongly resembles the D-alanyl-D-alanine natural conformation and this leads to total inactivation of the enzyme.

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A significant problem with all of these Inhibitors of Peptidoglycan Synthesis

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Is that they are acids and are easily eliminated via tubular excretion, so the half-life tends to be short.

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Sporicidal Agents

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Spores are inhibited by phenols (membrane disruptors) and cannot germinate in its presence but they do so once the phenol is removed. Spores are only destroyed by powerful oxidizing agents such as chlorine, chlorine dioxide, hypochlorite, ozone etc and by alkylating agents such as ethylene oxide, formaldehyde or glutaraldehyde.

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Self-promoted uptake (SPU)

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Occurs especially with the polycationic aminoglycoside inhibitors and involves destabilization and disorganization of the outer membrane by the displacement of Ca2+ and Mg2+ cations.

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1. Intrinsic Resistance
2. Acquired Resistance

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1. Is usually expressed by chromosomal genes
2. May result from mutations in chromosomal agents involved in chromosomal synthesis or by acquisition of plasmids or transposons

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Replicative Transposition

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At the co-integration stage, the transposable element is inserted into the plasmid DNA and then replication and insertion of a new transposon occur at a remote site in the acceptor plasmid

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Conservative Transposition

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The transposon and its own coded-for accompanying insertion enzymes simply insert the transposon into a plasmid or chromosomal DNA and the residual DNA is lost.