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1.
Microbiol Mol Biol Rev ; 66(4): 702-38, table of contents, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12456788

RESUMO

The bacterial acyltransferases of the SxxK superfamily vary enormously in sequence and function, with conservation of particular amino acid groups and all-alpha and alpha/beta folds. They occur as independent entities (free-standing polypeptides) and as modules linked to other polypeptides (protein fusions). They can be classified into three groups. The group I SxxK D,D-acyltransferases are ubiquitous in the bacterial world. They invariably bear the motifs SxxK, SxN(D), and KT(S)G. Anchored in the plasma membrane with the bulk of the polypeptide chain exposed on the outer face of it, they are implicated in the synthesis of wall peptidoglycans of the most frequently encountered (4-->3) type. They are inactivated by penicillin and other beta-lactam antibiotics acting as suicide carbonyl donors in the form of penicillin-binding proteins (PBPs). They are components of a morphogenetic apparatus which, as a whole, controls multiple parameters such as shape and size and allows the bacterial cells to enlarge and duplicate their particular pattern. Class A PBP fusions comprise a glycosyltransferase module fused to an SxxK acyltransferase of class A. Class B PBP fusions comprise a linker, i.e., protein recognition, module fused to an SxxK acyltransferase of class B. They ensure the remodeling of the (4-->3) peptidoglycans in a cell cycle-dependent manner. The free-standing PBPs hydrolyze D,D peptide bonds. The group II SxxK acyltransferases frequently have a partially modified bar code, but the SxxK motif is invariant. They react with penicillin in various ways and illustrate the great plasticity of the catalytic centers. The secreted free-standing PBPs, the serine beta-lactamases, and the penicillin sensors of several penicillin sensory transducers help the D,D-acyltransferases of group I escape penicillin action. The group III SxxK acyltransferases are indistinguishable from the PBP fusion proteins of group I in motifs and membrane topology, but they resist penicillin. They are referred to as Pen(r) protein fusions. Plausible hypotheses are put forward on the roles that the Pen(r) protein fusions, acting as L,D-acyltransferases, may play in the (3-->3) peptidoglycan-synthesizing molecular machines. Shifting the wall peptidoglycan from the (4-->3) type to the (3-->3) type could help Mycobacterium tuberculosis and Mycobacterium leprae survive by making them penicillin resistant.


Assuntos
Aciltransferases/metabolismo , Proteínas de Bactérias , Proteínas de Transporte/metabolismo , Hexosiltransferases , Muramilpentapeptídeo Carboxipeptidase/metabolismo , Mycobacterium tuberculosis/enzimologia , Resistência às Penicilinas/fisiologia , Penicilinas/farmacologia , Peptidil Transferases , Aciltransferases/genética , Sequência de Aminoácidos , Modelos Moleculares , Dados de Sequência Molecular , Proteínas de Ligação às Penicilinas , Penicilinas/metabolismo , Peptidoglicano/metabolismo
2.
Biochem J ; 361(Pt 3): 635-9, 2002 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-11802794

RESUMO

The product of the gene ponA present in cosmid MTCY21D4, one of the collection of clones representing the genome of Mycobacterium tuberculosis, has been named penicillin-binding protein 1* (PBP1*), by analogy to the previously characterized PBP1* of M. leprae. This gene has been overexpressed in Escherichia coli. His(6)-tagged PBP1* localizes to the membranes of induced E. coli cells. Its susceptibility to degradation upon proteinase K digestion of spheroplasts from E. coli expressing the protein supports the view that the majority of the protein translocates to the periplasmic side of the membrane. Recombinant PBP1* binds benzylpenicillin and several other beta-lactams, notably cefotaxime, with high affinity. Truncation of the N-terminal 64 amino acid residues results in an expressed protein present exclusively in inclusion bodies and unable to associate with the membrane. The C-terminal module encompassing amino acids 272-663 can be extracted from inclusion bodies under denaturing conditions using guanidine/HCl and refolded to give a protein fully competent in penicillin-binding. Deletion of Gly(95)-Gln(143) results in the expression of a protein, which is localized in the cytosol. The soluble derivative of PBP1* binds benzylpenicillin with the same efficiency as the full-length protein. This is the first report of a soluble derivative of a class A high-molecular-mass PBP.


Assuntos
Proteínas de Bactérias , Proteínas de Transporte/biossíntese , Proteínas de Transporte/química , Hexosiltransferases , Muramilpentapeptídeo Carboxipeptidase/biossíntese , Muramilpentapeptídeo Carboxipeptidase/química , Mycobacterium tuberculosis/metabolismo , Peptidil Transferases , Sequência de Aminoácidos , Antibacterianos/farmacologia , Western Blotting , Proteínas de Transporte/isolamento & purificação , Membrana Celular/metabolismo , Citosol/metabolismo , Endopeptidase K/metabolismo , Escherichia coli/metabolismo , Deleção de Genes , Glutamina/química , Glicina/química , Cinética , Dados de Sequência Molecular , Muramilpentapeptídeo Carboxipeptidase/isolamento & purificação , Fases de Leitura Aberta , Proteínas de Ligação às Penicilinas , Penicilinas/farmacologia , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes/metabolismo
3.
Int J Antimicrob Agents ; 13(2): 133-5, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10595573

RESUMO

The resistance of mycobacteria to beta-lactam antibiotics is attributed to their ability to synthesize beta-lactamase. In our previous studies, beta-lactam/beta-lactamase-inhibitor combinations suppressed the growth of several mycobacteria in axenic cultures and ampicillin/sulbactam was bactericidal to Mycobacterium tuberculosis H37Rv in vitro, and to Mycobacterium leprae multiplying in mouse foot-pads. Since both these organisms multiply in phagocytic cells in the host, it is important to know whether the drug combination is active against mycobacteria multiplying in macrophages. We tested the action of ampicillin/sulbactam against four potentially pathogenic (to humans or to animals) mycobacteria, M. simiae, M. haemophilum, M. avium, M. microti, when phagocytosed by mouse macrophages. Bacteria were exposed to monolayers of peritoneal macrophages harvested from BALB/c mice. Unphagocytosed bacilli were removed and three concentrations of ampicillin/sulbactam were tested. Optimum activity was observed at 100 mg/l which killed 58-97% of the mycobacteria within macrophages, as determined by the CFU. beta-Lactam/beta-lactamase-inhibitors, especially ampicillin/sulbactam, might provide an effective alternative therapy against infections caused by mycobacteria resistant to other drugs.


Assuntos
Ampicilina/farmacologia , Inibidores Enzimáticos/farmacologia , Mycobacterium/efeitos dos fármacos , Penicilinas/farmacologia , Sulbactam/farmacologia , Inibidores de beta-Lactamases , Animais , Contagem de Colônia Microbiana , Interações Medicamentosas , Humanos , Técnicas In Vitro , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium/crescimento & desenvolvimento , Fagocitose
4.
Int J Lepr Other Mycobact Dis ; 55(2): 322-7, 1987 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-3298478

RESUMO

Twelve beta-lactam antibiotics were tested for activity against Mycobacterium leprae growing in the foot pads of mice. Two cephalosporins (7-aminocephalosporanic acid and cefuroxime) and one cephamycin (cefoxitin) showed significant activity against M. leprae, and one penicillin (mezlocillin) exerted possible growth-promoting activity. These results suggest that particular molecular structures may be required for activity against M. leprae.


Assuntos
Antibacterianos/farmacologia , Mycobacterium leprae/efeitos dos fármacos , Animais , Cefoxitina/farmacologia , Cefuroxima/farmacologia , Cefalosporinas/farmacologia , Feminino , Hanseníase/tratamento farmacológico , Hanseníase/microbiologia , Mezlocilina/farmacologia , Camundongos , Mycobacterium leprae/crescimento & desenvolvimento , Penicilinas/farmacologia
5.
Int. j. lepr ; 14(n.esp): 37-41, Dec. 1946. tab
Artigo em Inglês | SES-SP, SES-SP, HANSEN, HANSENIASE, SESSP-ILSLACERVO, SES-SP | ID: biblio-1227304

RESUMO

Penicilin has been used for the treatment of seven lepromatous and one neural (Nt. in reaction) cases of leprosy in daily doses of 25,000 to 60,000 units over periods of 21 to 53 days for a total of 1,050,000 to 2,550,000 units. Three technics have been used: the first, intramuscular injections every 3 hours (8 injections per day and 168 in total); the second, intravenous drip, 8 to 10 hours a day; the third, one intramuscular injection a day, in oily suspension (mixture of peanut oil and beeswax). Observation was carried on for three months after treatments were completed. Except for general improvement and/or healing of ulcers in 4 patients, decrease of blood sedimentation rate in 5 patients (with increase in 2) and increase of red corpuscles and hemoglobin in 3 patients, no clinical, bacteriological, or immunological sign was recorded revealing any specific action of penicillin on Mycobacterium leprae or on the normal course of the disease either during the time of treatment or in the three months thereafter. In two cases with lepra reaction, penicillin appeared to have no effect. Four of the patients subjected to this treatment had strongly positive serological tests for syphilis (Wassermann, Hecht, Kahn Standard, Eagle, and Briceño Rossi reactions) with past history of syphilis. Treatment with penicillin did not modify the serological results. At the time this trial was ending, a similar article by Faget and Pogge (6) confirmed the major part of the observations herein described.


Assuntos
Humanos , Hansenostáticos/história , Hanseníase/tratamento farmacológico , Penicilinas/administração & dosagem , Penicilinas/farmacologia , Penicilinas/uso terapêutico
6.
Int. j. lepr ; 12(n.esp): 7-10, Dec. 1944.
Artigo em Inglês | SES-SP, SES-SP, HANSEN, HANSENIASE, SESSP-ILSLACERVO, SES-SP | ID: biblio-1227231
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