Bacitracin aureus

Acquired resistance to bacitracin has been observed in laboratory strains of Staph, aureus, but resistance has been unstable and no resistant mutants have yet been isolated in vivo. Gram-negative bacteria are intrinsically resistant to bacitracin, which inhibits the transfer of pentapeptide units to petidoglycan. 

Bacitracin inhibits gram-positive cocci, including Staphylococcus aureus, streptococci, a few gram-negative organisms, and one anaerobe, Clostridium difficile. 

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Inactivation of certain enzyme systems involved in the oxidative metabolism of sensitive organisms by polymyxin and colistin has also been reported. This, however, might be a secondary effect . Bacitracin has been reported to interfere with cell wall synthesis. It causes Staphylococcus aureus to lyse , to form protoplasts and to accumulate cell wall precursors " . The incorporation of radioactive amino acids into cell wall mucopeptides is inhibited. Bacitracin has further been found to prevent Staphylococcus aureus from synthesizing /3-galactosidase , yet it does not interfere with the incorporation of radioactive lysine into cells . In experiments with Staphylococcus aureus, bacitracin and penicillin were shown to share a common binding site on the membrane , a result which could not be confirmed in similar experiments with B. megateriumP . Recently a direct effect of bacitracin on the cytoplasmic membrane has been demonstrated, and it was suggested that the inhibition of cell wall synthesis could be a secondary effect . ... 

Early workers [29] found that, like benzylpenicillin, vancomycin, ristocetin and bacitracin, novobiocin caused an excessive accumulation of cell wall precursor, uridine diphosphate-7V-acetylmuramic acid-L-alanine-D-glutamic acid-L-lysine-D-alanine-D-alanine (UDP-MurNAc-L-ala-D-glu-L-lys-D-ala-D-ala) in Staph, aureus and it was thus considered that novobiocin was a specific inhibitor of peptidoglycan synthesis with an effect similar to that of penicillin. However, subsequent studies led to the withdrawal of this hypothesis [26], since novobiocin caused the accumulation of other precursor-type compounds and also strongly inhibited both nucleic acid and protein synthesis in this organism. Thus, accumulation of particular precursors does not necessarily reflect the site of action of an antibacterial agent [30]. 

Nalidixic acid 4.33) binds heavy metals between the carboxylic- and the oxo-groups (Crumplin, Midgley and Smith, 1980). It is not known if this plays a part in its biological action, which is inhibition of the synthesis of DNA (Section 4.0.5, p. 136). The antibacterial action of kojic acid (77./7), a pyrone extracted from certain fungi, is enhanced by metallic cations (Weinberg, 1957). Bacitracin, a polypeptide antibiotic (Section 13.2), loses its antibacterial action against Staph, aureus in the presence of EDTA the action is restored by bivalent cations (Adler and Snoke, 1962). 

As a consequence of penicillin interaction with the membrane of the cell, the pool level of an internal effector undergoes a slow change. The effector can be either an endogenous inducer, whose concentration rises as induction proceeds, or a co-repressor, whose falling concentration derepresses the penicillinase genes. Precursors to various cell-wall polymers are known to accumulate in S. aureus after exposure to penicillin [Park, 95-97 Ito and Saito, 98]. However, none of these compounds is a likely endogenous inducer within the cell, for similar compounds accumulate after treatment with other antibiotics which inhibit cell-wall synthesis (vancomycin, bacitracin) without induction of penicillinase. Penicillin-treated bacilli also do not appear to accumulate these compounds to the same extent as the staphylococci, though penicillinase induction follows. 

Cephalosporin C resembles penicillin in its ability to cause the accumulation of the uridine nucleotide (LVIII) in Staph, aureus and to bring about the lysis of growing organisms. Bacitracin behaves similarly, but it does not follow that this substance interferes with cell wall synthesis at the same point as the penicillinsi . 

Exit site infections are common and are recognized by redness, exudation and crusting. Topical agents applied to catheter exit site, such as povidone iodine, mupirocin, bacitracin zinc and polymixin B sulphate ointments have been proven effective [20, 21]. Oral rifampin or nasal mupirocin ointment reduced the incidence of S. aureus bacteremia [22]. 

Bacitracin has an antibacterial spectrum similar to that of penicillin and Paine (1951) found that it also resembled penicillin in that, although it had no effect upon the ability of Staph, aureus to accumulate glutamic acid when tested in washed suspensions, it had a progressively inhibitory action on this ability if it was added to the growth medium before harvesting. Paine found that strains which were resistant to penicillin were also resistant to bacitracin. 

In Staph, aureus the accumulation of glutamic acid is activated by either manganese or magnesium, and the process can be inactivated by 8-hydroxyquinoline which appears to act by chelating the metal component. If penicillin is added to the growth medium some time before the cells are harvested, it is found to exert a progressive inhibition on the ability of the harvested cells to accumulate glutamic acid. The effect is probably a secondary one. Similar results are obtained with bacitracin. 

Bacitracin has no effect on the accumulation of free glutamic acid or on glucose metabolism in washed suspensions of Staph, aureus (Paine, 1951) but, in concentrations 10-100 times greater than the bacteriostatic level, produces a marked inhibition of both protein and nucleic acid synthesis (Gale and Folkes, 1953b). There is no significant difference in the sensitivity of the two processes (see Fig. 31). No inhibitor has so far been found which will accomplish an inhibition of nucleic acid synthesis without affecting protein synthesis. 

Fig. 31. Inhibitory actions of bacitracin on Staph, aureus, o Net protein synthesis A incorporation of C Mabeled glutamic acid into cell protein, in absence of net protein synthesis nucleic acid synthesis. (Gale and Folkes, 1953b,c.)...

Penicillin has no effect on protein synthesis by washed Staph, aureus under the author s experimental conditions until the concentration is raised to a value several orders above the hmiting bactericidal level. It does, however, prevent the increase in rate of protein synthesis that normally follows the addition of purines and pyrimidines to the external medium. Its action is therefore somewhat similar to that of bacitracin except that it does not inactivate the protein-synthesizing mechanism of the cell which is not synthesizing nucleic acid. For the present its action is indicated in Fig. 33 as a blocking of the pre-protein template concerned with nucleic acid synthesis but the high concentrations and partial effects obtained would suggest that, if it does act in this way, it affects a specific part of the template system rather than the whole mechanism. This will be elaborated below. 

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