How antibiotics kill bacteria: from targets to networks - 0 views
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Most current bactericidal antimicrobials, which are the focus of this review, inhibit DNA synthesis, RNA synthesis, cell wall synthesis, or protein synthesis
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Quinolones are derivatives of nalidixic acid, which was discovered as a byproduct of chloroquine (quinine) synthesis
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Nalidixic acid and other first generation quinolones (i.e., oxolinic acid) are rarely used today owing to their toxicity17. Second (i.e., ciprofloxacin), third (i.e., levofloxacin) and fourth (i.e., gemifloxacin) generation quinolone antibiotics (Table 1) can be classified based on their chemical structure along with qualitative differences in how these drugs kill bacteria
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quinolone class of antimicrobials interferes with the maintenance of chromosomal topology by targeting DNA gyrase (topoisomerase II) and topoisomerase IV (topoIV), trapping these enzymes at the DNA cleavage stage and preventing strand rejoining
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DNA strand breakage occurs after the drug has bound the enzyme
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quinolone treatment is to generate double-stranded DNA breaks that are trapped by covalently (yet reversibly) linked topoisomerases whose functions are compromised
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eads to bacteriostasis and eventually cell deat
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DNA replication machinery becomes arrested at blocked replication forks, leading to inhibition of DNA synthesis, which immediately leads to bacteriostasis and eventually cell death
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inhibition by quinolones induces the DNA stress response (SOS response), in which RecA is activated by DNA damage and promotes auto-cleavage of the LexA repressor protein, inducing expression of SOS-response genes including DNA repair enzymes
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Preventing induction of the SOS response has also been shown to reduce the formation of drug-resistant mutants by blocking the induction of error-prone DNA polymerases34, homologous recombination20, and horizontal transfer of drug-resistance elements
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ifamycin drugs inhibit DNA-dependent transcription by stable binding, with high affinity, to the subunit (encoded by the rpoB gene) of a DNA-bound and actively-transcribing RNA polymerase enzyme
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a recently discovered class of RNA polymerase inhibitors (based on the compound CBR703) may inhibit elongation by allosteric modification of the enzyme
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requirement of rifamycins is that RNA synthesis has not progressed beyond the addition of two ribonucleotides
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bacterial cell is encased by layers of peptidoglycan (PG, or murein), a covalently cross-linked polymer matrix composed of peptide-linked β-(1–4)-N-acetyl hexosamine
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β-lactams and glycopeptides are among the classes of antibiotics that interfere with specific steps in homeostatic cell wall biosynthesis
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Successful treatment with a cell wall synthesis inhibitor can result in changes to cell shape and size, induce cellular stress responses, and culminate in cell lysis
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penicillins, carbapenems and cephalosporins
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inhibiting the peptide bond formation reaction catalyzed by transpeptidases, which are also known as penicillin-binding proteins
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the β-lactam drug molecule (containing a cyclic amide ring) is an analog of the terminal D-alanyl-D-alanine dipeptide of PG, and acts a substrate for the enzyme during the acylation phase of cross-link formation –- which disables the enzyme due to its inability to hydrolyze the bond created with the now ring-opened drug
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reduce cellular mechanical strength
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chemically-modified glycopeptides have been shown to directly interact with the transglycosylase enzyme
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lipopeptides (e.g., daptomycin) which affect structural integrity via their ability to insert into the cell membrane and induce depolarization
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Filamentation can occur, following activation of the DNA damage responsive SOS network of genes
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mRNA translation occurs over three sequential phases (initiation, elongation and termination) involving the ribosome
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The ribosome organelle is composed of two ribonucleoprotein subunits, the 50S and 30S
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Drugs that inhibit protein synthesis are among the broadest classes of antibiotics and can be divided into two subclasses: the 50S inhibitors and 30S inhibitors
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0S ribosome inhibitors work by physically blocking either initiation of protein translation
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or translocation of peptidyl-tRNAs, which serves to inhibit the peptidyltransferase reaction that elongates the nacent peptide chain
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30S ribosome inhibitors
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work by blocking the access of aminoacyl-tRNAs to the ribosome
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LysisRupture of the cell envelope leading to the expulsion of intracellular contents into the surrounding
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interferes with the stability of peptidyl-tRNA binding to the ribosome by inhibiting elongation factor-catalyzed translocation
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promoting tRNA mismatching which can result in protein mistranslation
