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PubMed1976

Characterization of mutations in the penicillinase operon Staphylococcus aureus.

Mutant penicillinase plasmids, in which penicillinase synthesis is not inducible by penicillin or a penicillin analogue, were examined by biochemical and genetic analyses. In five of the six mutants tested, penicillinase synthesis could be induced by growth in the presence of 5-methyltryptophan. It is known that the tryptophan analogue 5-methyltryptophan is readily incorporated into protein by S. aureus and that staphylococcal penicillinase lacks tryptophan. 5-methyltryptophan seems to induce penicillinase synthesis in wild-type plasmids by becoming incorporated into the repressor and thereby inactivating the operator binding function of the penicillinase repressor. Therefore, induction of penicillinase synthesis in the mutant plasmids by 5-methyltryptophan strongly suggests that the noninducible phenotype of these five plasmids is due to a mutation that inactivates the effector binding site of the penicillinase repressor (i.e., the five mutant plasmids carry an iS genotype for the penicillinase repressor). This conclusion was supported by heterodiploid analysis. The mutant plasmid that did not respond to 5-methyltryptophan either produces an exceedingly low basal level of penicillinase or does not produce active enzyme. This plasmid seems to carry a mutation in the penicillinase structural gene or in the promoter for the structural gene. Thus, a genetic characterization of many mutations in the penicillinase operon can be accomplished easily and rapidly by biochemical analysis.

Extrachromosomal Inheritance↗

PubMed1996

Importance of penicillinase production for activity of penicillin alone or in combination with sulbactam in experimental endocarditis due to methicillin-resistant Staphylococcus aureus.

The activity of penicillin, alone and in combination with sulbactam, against a heterogeneously methicillin-resistant, penicillinase-producing clinical isolate of Staphylococcus aureus and its penicillinase-negative derivative was investigated in vitro and in a rabbit experimental endocarditis model. Penicillin was significantly more effective than vancomycin against the penicillinase-negative derivative in vivo (P < 0.001), and it sterilized 25% of the vegetations. The combination of penicillin and sulbactam exhibited an in vivo synergistic effect on the penicillinase-producing strain (P < 0.01) but did not produce any advantage over treatment with vancomycin, even when a high dose of sulbactam was used (100 mg/kg of body weight every 6 h). This combination was significantly less effective against the penicillinase-producing strain than was penicillin alone against the penicillinase-negative derivative (P < 0.03). In addition, the most resistant subpopulation of the surviving bacteria, which grew on agar containing 16 micrograms of methicillin per ml, was detected in 5 of 6 animals treated with penicillin and a high dose of sulbactam against the penicillinase-producing strain compared with only 1 of 12 animals treated with penicillin alone against the penicillinase-negative derivative (P < 0.01). We conclude that penicillin is highly effective against penicillinase-negative methicillin-resistant S. aureus and that penicillinase production, rather than methicillin resistance, appears to be the limiting factor for the activity of the penicillin-sulbactam combination against penicillinase-producing, methicillin-resistant S. aureus.

Animals↗

PubMed1982

Epidemiology of penicillinase-producing Neisseria gonorrhoeae infections: analysis by auxotyping and serogrouping.

Auxotyping and serogrouping by coagglutination were used to characterize penicillinase-producing Neisseria gonorrhoeae and penicillinase-negative isolates from the state of Washington, Shreveport (Louisiana), and the Far East. Fifty-four of 75 penicillinase-producing isolates (72 per cent) from Washington required proline for growth and were serogroup W-l (Pro-1), the predominant type of penicillinase-producing strains in the Philippines; none of 86 penicillinase-negative isolates from Washington was Pro-1 (P less than 0.0001). All 38 penicillinase-producing isolates from Shreveport required proline and were serogroup W-11 (Pro-11); five of 26 penicillinase-negative isolates (19 per cent) from Shreveport were also Pro-11 (P less than 0.0001) but had antigenic specificities within serogroup W-ll that distinguished them from the penicillinase-producing isolates. We conclude that the Washington and Shreveport outbreaks resulted from the spread of imported strains rather than transmission of penicillinase-encoding plasmids to indigenous gonococci. The Shreveport outbreak involved a single strain of penicillinase-producing N, gonorrhoeae and probably originated from a common source, whereas several types were involved in the multiple-source Washington outbreak, indicating repeated introduction of new strains.

Disease Outbreaks↗

PubMed1975

Further evidence for a partially folded intermediate in penicillinase secretion by Bacillus licheniformis.

Protoplasis of Bacillus licheniformis 749/C (a mutant constitutive for penicillinase production) continued to synthesize and release penicillinase in hypertonic growth medium in the presence of trypsin and chymotrypsin at 25 mug each per ml. When the protoplasts were stripped of about half of their membrane-bound penicillinase by pretreatment at pH 9.5 or with a higher level of trypsin, penicillinase activity no longer increased in the presence of the proteases. This effect was immediately eliminated after addition of soybean trypsin inhibitor. These proteases do not significantly inhibit general protein synthesis. Stripped protoplasts of strain 749/C and of uninduced strain 749 (unable to synthesize penicillinase) were incubated with 50 mug of chymotrypsin per ml, and the supernatent fluids were examined immunochemically for peptides derived from the penicillinase chain. Such fargments were found only with the protoplasts capable of synthesizing penicillinase (strain 749/C). The direct detection of the products of protease degradation of a susceptible form of penicillinase provides strong evidence that, in stripped protoplasts of B. licheniformis 749/C, penicillinase synthesis continues in the presence of trypsin or chymotrypsin and that, in these modified membranes, the protease is able to act on an early form of the enzyme that has not yet attained the protease-resistant conformation characteristic of the membrane-bound and exopenicillinases. This finding is discussed in terms of the current models of penicillinase secretion.

Animals↗

PubMed1983

The penicillinase of Bacillus licheniformis is an outer membrane protein in Escherichia coli.

The cloned gene coding for Bacillus licheniformis penicillinase (penP) was introduced into Escherichia coli in a heat-inducible lambda Qam vector. After induction, significant amounts of penicillinase were synthesized in the new host. The cellular location of the penicillinase was found to be almost exclusively the outer membrane fraction of E. coli, and virtually no soluble penicillinase was found. According to sodium dodecyl sulfate-gel electrophoresis, the size of the penicillinase from E. coli was identical to that of the membrane-bound form of the B. licheniformis penicillinase. Gel filtration in the presence of Triton X-100 suggested that the penicillinase from E. coli had amphiphilic properties, as does B. licheniformis membrane penicillinase. These results show that the export of the penicillinase to the outer membrane of E. coli involves the cleavage of the signal peptide from the prepenicillinase, giving an outer membrane component indistinguishable from the membrane penicillinase of B. licheniformis.

Bacillus↗

PubMed1964

METABOLIC CONTROL OF PENICILLINASE BIOSYNTHESIS IN BACILLUS CEREUS.

Yip, Lily C. (University of Cincinnati, Cincinnati, Ohio), Ramesh Shah, and Richard A. Day. Metabolic control of penicillinase biosynthesis in Bacillus cereus. J. Bacteriol. 88:297-308. 1964.-Penicillinase production in strains 5 and 5/B of Bacillus cereus in response to treatment by 6-aminopenicillanic acid (APA), penicillin G, (6-N-alpha-(p-benzyloxyphenoxy)-propionylamino-penicillanic acid, and cephalosporin C (CC) was found to be analogous to that seen in constitutive strains. Strain 5 did not release penicillinase into the medium to any great extent. Penicillinase production and the effect of the above penicillins on it were found to decline with increasing density of the culture. The penicillins were shown to accelerate or retard the production of penicillinase activity in strain 5 cells during pretreatment at 0 C and during incubation at 37 C. Strains 5 and 5/B gave qualitatively similar responses to penicillin treatment. At 0 C, the specific activity of penicillinase in strain 5 passes through a period of rapid increase at 0 hr and a period of little change at approximately 1 hr, followed by an increased rate of change towards 2 hr. The effect of APA or CC on specific activity of strain 5 cells during treatment at 0 C could not be reversed by one another, but Hg could reverse the increase caused by CC to some extent and the repression caused by APA. The production of penicillinase in the microconstitutive strain 5 of Bacillus cereus in response to treatment with CC was influenced by various inhibitors. 8-Azaguanine inhibited the production of the enzyme both during a pretreatment of the cells with CC at 0 C and during the subsequent incubation at 37 C. Actinomycin D, 6-azauracil, 6-thioguanine, and 2-thiocytosine inhibit the increase in penicillinase arising after the pretreatment at 0 C. 6-Azathymine has very little effect on the change of penicillinase activity. The CC-induced change occurring during the 0 C period was postulated to be a process at the level of protein biosynthesis itself; change at 37 C, constituting a delayed response, was considered a process at the level of messenger ribonucleic acid synthesis.

Azaguanine↗

PubMed1987

Immunological properties of a penicillinase produced by Alcaligenes denitrificans subsp. xylosoxydans.

Rabbit antiserum was prepared to the penicillinase of Alcaligenes denitrificans subsp. xylosoxydans GN14062. The antibody gave a single precipitin line in double immunodiffusion assays with the penicillinases from strain GN14062 and from two other A. denitrificans subsp. xylosoxydans strains. The precipitin line given by the GN14062 enzyme gave a reaction of complete identity with the precipitin lines of the penicillinases from the other A. denitrificans subsp. xylosoxydans strains. Furthermore, activity of the penicillinases from all three A. dentrificans subsp. xylosoxydans strains was neutralized by the antiserum to the GN14062 enzyme. Thus it was proved that the penicillinases produced by the three A. denitrificans subsp. xylosoxydans strains were immunologically identical. Penicillinases types I, II, III, IV, V, SHV-1, TEM-1, TEM-2, and the chromosomal penicillinases of Klebsiella pneumoniae GN69 and A. faecalis GN14061 formed no immunoprecipitate with, nor were neutralized by, the antiserum to the GN14062 enzyme. From these results, it was concluded that the penicillinase produced by A. denitrificans subsp. xylosoxydans was immunologically distinct from the penicillinases produced by these other bacteria.

Alcaligenes↗

PubMed1985

Localisation of the penicillinase gene in naturally occurring Staphylococcus aureus strains.

Localisation of the penicillinase gene was studied in a total of 104 inducible Staphylococcus aureus strains selected from 10,229 bacteraemia strains isolated in the years 1957-1981. The strains represented all possible combinations of the most common patterns of phage type and susceptibility to heavy metals (cadmium, arsenate and mercury) and antibiotics. The material was further supplemented with epidemically occurring strains. Localisation of the penicillinase gene was established by isolation of penicillinase-negative variants and analysis of DNA-bands on CsCl gradients and gel-electrophoresis. Fifty-five strains contained a penicillinase plasmid; 49 had a chromosomal location. The genetic location was mainly connected with phage types. All strains belonging to the 83A complex and the majority of the strains of the 52, 52A, 80, 81 complex and of phage type 95 contained a penicillinase plasmid, whereas chromosomal location was found in all strains of group II and of the 94,96 complex. In all strains but three (group III) the resistances to heavy metals were located on the penicillinase plasmid. Association between the penicillinase plasmid and genes coding for resistance to other antibiotics was found in one tetracycline resistant strain only. Three micro-constitutive strains had chromosomally located penicillinase gene, whereas one macro-constitutive strain contained a penicillinase plasmid.

Arsenic↗

PubMed1970

Variant of penicillinase mediated by an R factor in Escherichia coli.

The penicillinase from an Escherichia coli strain harboring an R factor R(GN823) was purified and its properties were compared with those of a known type I penicillinase mediated by R factors. The molecular weight and S(20,w) of the enzyme were 22,600 and 2.42S, respectively. The isoelectric point of the enzyme was 6.9. These values are clearly different from those of type I penicillinase. The specific activity of the enzyme was 84,700 units per mg of the purified enzyme protein, which is about 20 times higher than that of the type I penicillinase. However, similarities were observed between the enzyme and the type I-penicillinase at optimal pH (6.5 to 7.0), optimal temperature (40 to 45C), substrate specificity, Michaelis constants for penicillins and cephaloridine, and effect of inhibitors. Furthermore, antiserum against type I penicillinase showed cross-reaction against this enzyme. The enzyme was named type Ib penicillinase, and the original type I penicillinase was renamed type Ia-penicillinase.

Agar↗

PubMed1998

The impact of penicillinase on cefamandole treatment and prophylaxis of experimental endocarditis due to methicillin-resistant Staphylococcus aureus.

Beta-lactams active against methicillin-resistant Staphylococcus aureus (MRSA) must resist penicillinase hydrolysis and bind penicillin-binding protein 2A (PBP 2A). Cefamandole might share these properties. When tested against 2 isogenic pairs of MRSA that produced or did not produce penicillinase, MICs of cefamandole (8-32 mg/L) were not affected by penicillinase, and cefamandole had a > or =40 times greater PBP 2A affinity than did methicillin. In rats, constant serum levels of 100 mg/L cefamandole successfully treated experimental endocarditis due to penicillinase-negative isolates but failed against penicillinase-producing organisms. This suggested that penicillinase produced in infected vegetations might hydrolyze the drug. Indeed, cefamandole was slowly degraded by penicillinase in vitro. Moreover, its efficacy was restored by combination with sulbactam in vivo. Cefamandole also uniformly prevented MRSA endocarditis in prophylaxis experiments, a setting in which bacteria were not yet clustered in the vegetations. Thus, while cefamandole treatment was limited by penicillinase, the drug was still successful for prophylaxis of experimental MRSA endocarditis.

Animals↗

PubMed1980

Penicillinase-producing Neisseria gonorrhoeae in the Netherlands: epidemiology and genetic and molecular characterization of their plasmids.

Penicillinase-producing Neisseria gonorrhoeae strains were isolated in the Netherlands with increasing frequency during the period of 1976 to 1979. About 3% of the gonococci isolated in the first half of 1979 produced penicillinase. In contrast to the period of 1976 to 1977, most penicillinase-producing N. gonorrhoeae infections during the period of 1978 to 1979 were contracted in the Netherlands. The results of genetic and molecular studies on 80 penicillinase-producing N. gonorrhoeae strains were similar to earlier observations of others: resistance plasmids of only two sizes, 4.5 and 3.3 megadaltons (Md), occurred in penicillinase-producing N. gonorrhoeae strains, and these encoded for the TEM-1 enzyme. The 4.5-Md plasmid could be transferred to Escherichia coli when it coexisted with a plasmid of 24 Md. The latter plasmid was present in the vast majority of the strains carrying the 4.5-Md plasmid. One strain carried a cryptic 7.5-Md plasmid in addition to the commonly found 2.5-Md plasmid. Two penicillinase-producing strains of Haemophilus parainfluenzae isolated were found to carry a 3.3-Md plasmid species which was indistinguishable from the 3.3-Md gonococcal resistance plasmids. No plasmid deoxyribonucleic acid was found in two strains of penicillinase-producing Branhamella catarrhalis, and these strains produced a penicillinase different from the TEM-1 enzyme.

Anti-Bacterial Agents↗

PubMed1968

Characteristics of secretion of penicillinase, alkaline phosphatase, and nuclease by Bacillus species.

The distribution of alkaline phosphatase and nuclease activity between cells and medium was examined in one strain of Bacillus licheniformis and four strains of B. subtilis. Over 95% of both activities was found in the medium of the B. licheniformis culture, but in the B. subtilis cultures the amount of enzyme activity found in the medium varied with the strain and the enzyme considered. B. licheniformis 749 and its penicillinase magnoconstitutive mutant 749/C were grown in continuous culture with phosphorous as the growth-limiting factor, and the kinetics of penicillinase formation and secretion were examined. Nutrient arrest halted secretion (usually after a lag of about 30 min) in both the inducible and constitutive strains. Chloramphenicol did not eliminate secretion, but under certain circumstances reduced its rate. In the inducible strain treated with a low level of inducer, the rate of secretion was more affected by the rate of synthesis than by the level of cell-bound enzyme. During induction, the onset of accretion of cell-bound penicillinase and secretion of the exoenzyme were nearly simultaneous. It seems unlikely that a long-lived, membrane- or cell-bound intermediate is mandatory in the secretion of the three enzymes by Bacillus species. In the case of penicillinase secretion, there are at least two different phases. When penicillinase synthesis is proceeding rapidly, the rate of secretion is five to six times greater at equivalent concentrations of membrane-bound penicillinase than it is when penicillinase synthesis is reduced. The data require that any membrane-bound intermediate in the formation of exoenzyme be much shorter-lived in cells with a high rate of synthesis than in cells with a low rate. Either there are two separate routes for the secretion of penicillinase or the characteristics of the process vary substantially between the early stages and the declining phase of induction.

Alkaline Phosphatase↗

PubMed1970

Penicillinase Studies on L-Phase Variants, G-Phase Variants, and Reverted Strains of Staphylococcus aureus.

L-phase variants and small colony (G-phase) variants derived from penicillinase-producing Staphylococcus aureus strains were tested for penicillinase (beta lactamase) production. A refined variation of the modified Gots test for penicillinase was used to demonstrate penicillinase synthesis. Penicillinase synthesis was reduced in L-phase variants and G-phase variants when compared to parental strains. After reversion of variants to vegetative stages had been induced, revertants were tested for production of penicillinase, coagulase, and alpha hemolysin, mannitol fermentation, and pigment production, and comparisons were made between parent and reverted vegetative forms. All revertants of G-phase variants retained penicillinase activity. Most revertants of L-phase variants showed reduction or loss of penicillinase activity. Retention of coagulase activity, alpha hemolysin production, mannitol fermentation, pigmentation, and phage type varied among revertants.

Journal Article↗

PubMed1964

NATURE OF THE DETERMINANT CONTROLLING PENICILLINASE PRODUCTION IN STAPHYLOCOCCUS AUREUS.

Harmon, Shirley A. (Ohio State University, Columbus), and Jack N. Baldwin. Nature of the determinant controlling penicillinase production in Staphylococcus aureus. J. Bacteriol. 87:593-597. 1964.-From three penicillinase-producing strains of Staphylococcus aureus 38 penicillin-sensitive mutants were isolated. With phages 80 and 53 of the International Typing Series, each of these mutants was a competent recipient of the penicillinase marker from the parent strains. Although numerous reciprocal transductions were performed between penicillin-sensitive mutants, no penicillinase-producing recombinants were observed. Reversion of the penicillinase-negative mutants to capacity to produce penicillinase was never observed. When tested for 50 distinctive physiological characteristics, the mutants generally were similar to the parent strains except for resistance to penicillin. One penicillin-sensitive mutant failed to produce detectable amounts of five exoenzymes. By treating resistant strains with acridine orange, it was possible to isolate sensitive strains at a frequency that was 60 times greater than the spontaneous mutation rate. Thus, the determinant controlling the capacity of strains of S. aureus to produce penicillinase appears to be a cytoplasmic element.

Acridines↗

PubMed1965

NATURE AND INTERACTIONS OF THE GENETIC ELEMENTS GOVERNING PENICILLINASE SYNTHESIS IN STAPHYLOCOCCUS AUREUS.

Novick, Richard P. (The Rockefeller Institute, New York, N.Y.), and Mark H. Richmond. Nature and interactions of the genetic elements governing penicillinase synthesis in Staphylococcus aureus. J. Bacteriol. 90:467-480. 1965.-It has been found previously that penicillinase-producing strains of Staphylococcus aureus each harbor an extrachromosomal element, or plasmid, which apparently carries all the genetic information necessary for penicillinase synthesis. These plasmids behave in a manner consistent with their being small chromosomelike structures in that they comprise linkage groups containing several markers and in that they undergo such genetic events as mutation, segregation, and recombination. There is currently no evidence for conjugal cell-cell transfer of the plasmids or for a state of stable integration into the staphylococcal chromosome. A certain amount of variability has been encountered among the penicillinase plasmids harbored by different staphylococcal strains. It has been found that: (i) there are at least three molecular variants of the enzyme itself; (ii) most, but not all, of the penicillinase plasmids carry a genetic determinant of resistance to mercuric ion; (iii) plasmids carried by a very small number of the strains bear a determinant of resistance to erythromycin; (iv) the plasmids determine the fraction of penicillinase excreted into the medium during growth, and this also varies from strain to strain. The penicillinase plasmids appear to behave as integral genetic structures. The entire known linkage group is transduced intact, and is occasionally lost completely as a spontaneous occurrence during the growth of the organisms. Rarely, the plasmid markers dissociate during transduction, resulting in transduced clones which have inherited only a part of the plasmid linkage group. Similarly, dissociation occurs as a spontaneous event during normal growth, also resulting in rare clones which appear to have lost one or more but not all of the plasmid markers. When crosses are performed between two plasmid-harboring strains, a plasmid heterozygote is formed. In most cases, this persists for only one or a few cell divisions before segregating, with or without the formation of recombinant plasmids. In two instances thus far observed, the heterozygote persists as a stable plasmid heterodiploid, in which the continued presence of both plasmids can be readily demonstrated. The fate of the heterozygote, i.e., early segregation or persistence as a heterodiploid, depends upon which particular pair of plasmids is involved in the cross. This observation has led to the hypothesis of a plasmid-linked determinant of plasmid compatibility. A pair of plasmids is considered compatible if it can form a stable heterodiploid, incompatible if it cannot.

Cell Division↗

PubMed1983

Accumulation of glyceride-modified pre-penicillinase of Bacillus licheniformis in Escherichia coli treated with globomycin.

The membrane penicillinase of Bacillus licheniformis is a glyceride-cysteine lipoprotein whose NH2 terminus is analogous to the major outer membrane lipoprotein of Escherichia coli. When E. coli cells producing B. licheniformis penicillinase were treated with the antibiotic, globomycin, a precursor of the penicillinase, pre-penicillinase, accumulated in the cell. It could be immunoprecipitated with anti-penicillinase antibodies; it contained palmitate; and one of its two cysteine residues was modified by glycerol. The action of globomycin, probably indirectly, also activates protease which acts differently on the pre-penicillinase than does the signal peptidase. The results strongly indicate that the pre-penicillinase is processed by the globomycin-sensitive signal peptidase in E. coli, and the modification of precursor by lipid precedes removal of the signal peptide as it does with the membrane lipoproteins of E. coli.

Anti-Bacterial Agents↗

PubMed1970

Regulation of penicillinase synthesis: evidence for a unified model.

The kinetics of penicillinase induction in Bacillus cereus 569 was investigated. An increase in the rate of penicillinase synthesis was demonstrated within 30 sec of the addition of inducer (benzylpenicillin); however, the maximum induced rate of penicillinase synthesis was not attained until at least 30 min after the addition of inducer. In contrast to earlier claims, a quantitative estimate showed that the penicillinase messenger ribonucleic acid (mRNA) half-life is approximately 2 min. These findings strongly suggest that the rate of synthesis of penicillinase mRNA increases continuously during most of the 30-min latent period. A model for the regulation of penicillinase synthesis in three gram-positive organisms is presented which is consistent with a nondiffusible inducer, a short-lived mRNA, a relatively long latent period (i.e., an apparently slow inactivation of penicillinase repressor), and the existence of at least two regulatory genes.

Bacillus cereus↗

PubMed1981

Cloning of the genes for penicillinase, penP and penI, of Bacillus licheniformis in some vector plasmids and their expression in Escherichia coli, Bacillus subtilis, and Bacillus licheniformis.

By using plasmid pMB9, penicillinase genes (penP and penI) from both the wild-type and constitutive strains of Bacillus licheniformis 9945A were cloned in EScherichia coli. When a low-copy-number plasmid was used, both wild-type and constitutive penicillinase genes could be transferred into Bacillus subtilis. However, when a high-copy-number plasmid was used, only the genes of the wild type could be transferred. These recombinant plasmids in B. subtilis could all be transferred by the protoplast transformation procedure into B. licheniformis. Transformants of E. coli were resistant to ampicillin (20 micrograms/ml) in spite of the low penicillinase activities (7 U/mg of cells). However, transformants of B. subtilis and B. licheniformis were sensitive to ampicillin (20 micrograms/ml) even in high penicillinase activities (more than 10,000 U/mg of cells). The secretion of penicillinase was rarely observed in E. coli. In contrast, penicillinases secreted from transformants of B. subtilis and B. licheniformis were around 30 and 60% of the total activities, respectively. We took advantage of the plasmids to permit the construction of hetero- and mero-polyploid structures in host cells, and we discuss a regulatory mechanism of penicillinase synthesis in B. licheniformis.

Bacillus↗