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Category: Industrial Microbiology; Clinical Microbiology
Mechanisms of Action, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555816445/9781555819019_Chap07-1.gif /docserver/preview/fulltext/10.1128/9781555816445/9781555819019_Chap07-2.gifAbstract:
Many compounds and processes have been identified as antimicrobial agents. For the purpose of this review, they are classified as anti-infective or biocides. Anti-infectives have been identified and developed for specific use in the control of microbial infections while having limited or no toxic effect on the host. This chapter considers, for comparison, the modes of activity of various anti-infectives, which are discussed as antibacterials (antibiotics), antiviral drug, antifungal drug, and antiprotozoal drug agents. The modes of action of biocides are discussed under four main classifications, based on their primary mechanisms of action: oxidizing agents, cross-linking or coagulating agents, and transfer-of-energy and other structure-disrupting agents. The antimicrobial effects of most biocides and biocidal processes are generally broad spectrum, with multiple effects on target microorganisms and their associated macromolecules. Further, in some cases, specific key targets for some biocides have been identified, and they are known targets for some antibacterial antibiotics (e.g., triclosan). The specific effects on microbial macromolecules are discussed in the consideration of heat. The biocides discussed in this chapter have been described as having as their primary mode of action the disruption of the structures and functions of lipid membranes. Until recently, it was widely considered that biocides had more nonspecific modes of action, in contrast to antibiotics and other anti-infective drugs.
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Primary bacterial targets of key antibiotics.
The structures of amino acids and peptide bonding. Representations are shown of two amino acids condensing to form a dipeptide linked by a peptide bond. Examples of the various side groups (R) that define the different amino acids are also shown.
Examples of sugars, polysaccharides, and glycosidic bonds. The polysaccharides shown are both polymers of glucose but vary in the structures of the glycosidic bond linkages.
The basic structures of fatty acids. The numbers of carbons in the fatty acid structure can vary, and examples of stearic acid (C18) and palmitoleic acid (C16:1) are shown.
Examples of various types of lipids. The general structures of a triglyceride, a glycolipid (with one sugar linked to two fatty acids), and a sterol (ergosterol) are shown.
The basic structures of nucleotides. The structure consists of a sugar (ribose or deoxyribose) linked to a phosphate (only a monophosphate group is illustrated) and various bases (pyrimidines and purines).
Nucleotide structures. ATP (top left) is a mononucleotide, while DNA (bottom) and RNA (top right;simple structure shown) are polynucleotides. DNA is a double-stranded polynucleotide (with hydrogen bonding holding the two parallel strands together), while the representation of a tRNA polynucleotide shows single- and double-stranded sections (with hydrogen-bonded bases shown as lines between the strands).
The major target sites for oxidizing agents on the structure of DNA (a) and, specifically, on the nucleotide bases (b), with examples of the pyrimidine bases thymine and cytosine.
Reaction of ethylene oxide with guanine.
Reaction of ethylene oxide with amino acid side chains.
Amino acids, showing free amine groups (circled), susceptible to cross-linking by aldehydes. The side chain amino group of lysine is particularly sensitive;in addition, other amino groups that are not associated with peptide bonds and therefore are at the ends of proteins and peptides are also susceptible.
A typical cross-linking reaction with formaldehyde between a lysine amino acid side chain and an adjacent peptide bond. The sensitive amino group (NH2) of the lysine residue is shown, as well as the reaction of the N atom of the peptide bond with formaldehyde to form a methylene bridge.
A typical cross-linked reaction by glutaraldehyde between two amino acids in adjacent proteins. The reactive amino group in each amino acid reacts with the aldehyde group on each end of the glutaraldehyde molecule, leading to the formation of a flexible methylene bridge.
Heat denaturation of DNA (above) and protein (below). As the temperature rises, the hydrogen bonding between the DNA nucleotides is broken, with adeninethymine linkages being particularly sensitive. Above 85°C, the strands are further denatured and eventually separate. On cooling, the DNA strands can reanneal, but fragmentation also occurs due to breaks in the sugar-phosphate backbone. Similarly, the noncovalent interactions in proteins are disrupted, causing them to lose their functional structures and assume their primary structures. In some cases, on cooling, the protein may refold to its original structure, but most proteins reassemble into inactive forms and precipitate. Breakage of peptide bonds that link amino acids also occurs, leading to peptide fragmentation.
The effects of ionizing and nonionizing radiation on a target atom. Nonionization (A) causes the excitation of electrons due to absorption of energy, which, if sufficient, will cause electrons to move to a higher, outer energy orbital. In the case of ionization (B), sufficient energy is absorbed to expel the electron from the atom entirely. In both cases, these effects destabilize the individual atoms, the molecules they are part of, and the interactions between those molecules.
The production of thymine dimers between adjacent thymine bases in DNA.
The mode of action of acridine dyes. The acridine molecule shown (proflavine) intercalates between the nucleotide bases in the DNA molecule, causing disruption of structure and function.
The reaction of metal ions on exposed sulfhydryl groups on cysteine amino acid within a peptide.
The effects of biocides on cytoplasmic membranes. The biocide can have subtle effects on membrane functions, including surface- and membrane-associated proteins (involved in substrate transport across the membrane or other enzymatic reactions) and disruption of the PMF. The biocide can also have more drastic effects on the lipid membrane structure, leading to an increase in permeability and cytoplasmic leakage; further damage can eventually lead to cell lysis.
Comparison of anti-infectives and biocides
Widely used antibiotics (antibacterials) and their mechanisms of action
Widely used antifungal drugs and mechanisms of action
Widely used antiviral drugs and mechanisms of action
Widely used antiparasitic drugs and mechanisms of action
Biocides with an oxidizing-agent-based mode of action
Examples of products observed on reaction of oxidizing agents with amino acids
Biocides with cross-linking- or coagulation-based modes of action
Biocidal processes with transfer-of-energy-based modes of action
Biocides that act by disrupting the structures and functions of macromolecules