Bacterial proteases: current therapeutic use and future prospects for the development of new antibiotics

被引:121
作者
Supuran, CT [1 ]
Scozzafava, A [1 ]
Mastrolorenzo, A [1 ]
机构
[1] Univ Florence, Lab Chim Inorgan & Bioinorgan, I-50121 Florence, Italy
关键词
AAA protease; antibiotics; botulinum neurotoxins; Clostridium collagenase; cysteine protease; degP; enzyme inhibitor; metalloprotease; serine protease; sortase; tetanus neurotoxin;
D O I
10.1517/13543776.11.2.221
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Proteases of the serine-, cysteine- and metallo- type are widely spread in many pathogenic bacteria, where they play critical functions related to colonisation and evasion of host immune defences, acquisition of nutrients for growth and proliferation, facilitation of dissemination, or tissue damage during infection. Since all the antibiotics currently used clinically share a common mechanism of action, i.e., inhibition of bacterial cell wall biosynthesis, resistance to these pharmacological agents represents a serious medical problem, which might be resolved by using a new generation of antibiotics with a different mechanism of action. Bacterial protease inhibitors constitute an interesting possibility, due to the fact that many specific and ubiquitous proteases have recently been characterised in some detail in both Gram-positive and Gram-negative pathogens. Unfortunately, at this moment few potent, specific inhibitors for such bacterial proteases have been reported, except for signal peptidase, clostripain, Clostridium histolyticum collagenase, botulinum neurotoxin and tetanus neurotoxin inhibitors (but such protease inhibitors are not used clinically for the moment). No inhibitors of the critically important and ubiquitous AAA proteases, degP or sortase have been reported, although such compounds would presumable constitute a new class of highly effective antibiotics. On the other hand, several bacterial proteases, such as the Clostridium histolyticum collagenase, or the botulinum neurotoxin A possess therapeutic applications per se for the treatment of some disease or for the preparation of vaccines. This review presents the state of the art ina the design of such enzyme inhibits with potential therapeutic applications as well as recent advances in the use of some of thee proteases in therapy.
引用
收藏
页码:221 / 259
页数:39
相关论文
共 214 条
[41]   Active-site variants of Streptomyces griseus protease B with peptide-ligation activity [J].
Elliott, RJ ;
Bennet, AJ ;
Braun, CA ;
MacLeod, AM ;
Borgford, TJ .
CHEMISTRY & BIOLOGY, 2000, 7 (03) :163-171
[42]   Use of cycloserine-cefoxitin-fructose agar and L-proline-aminopeptidase (PRO Discs) in the rapid identification of Clostridium difficile [J].
Fedorko, DP ;
Williams, EC .
JOURNAL OF CLINICAL MICROBIOLOGY, 1997, 35 (05) :1258-1259
[43]   Dual protease inhibitor therapy in HIV-infected patients: Pharmacologic rationale and clinical benefits [J].
Flexner, C .
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 2000, 40 :649-674
[44]   The crystal structure of a penicilloyl-serine transferase of intermediate penicillin sensitivity -: The DD-transpeptidase of Streptomyces K15 [J].
Fonzé, E ;
Vermeire, M ;
Nguyen-Distèche, M ;
Brasseur, R ;
Charlier, P .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (31) :21853-21860
[45]   Molecular evolution of the pathogenicity island of enterotoxigenic Bacteroides fragilis strains [J].
Franco, AA ;
Cheng, RK ;
Chung, GT ;
Wu, SG ;
Oh, HB ;
Sears, CL .
JOURNAL OF BACTERIOLOGY, 1999, 181 (21) :6623-6633
[46]  
FRERE JM, 1998, HDB PROTEOLYTIC ENZY, pCH145
[47]   REFINED STRUCTURE OF ALPHA-LYTIC PROTEASE AT 1.7-A RESOLUTION - ANALYSIS OF HYDROGEN-BONDING AND SOLVENT STRUCTURE [J].
FUJINAGA, M ;
DELBAERE, LTJ ;
BRAYER, GD ;
JAMES, MNG .
JOURNAL OF MOLECULAR BIOLOGY, 1985, 184 (03) :479-502
[48]  
FUKUSHIMA J, 1998, HDB PROTEOLYTIC ENZY, pCH367
[49]   Glutamyl hydrolase: pharmacological role and enzymatic characterization [J].
Galivan, J ;
Ryan, TJ ;
Chave, K ;
Rhee, M ;
Yao, R ;
Yin, DZ .
PHARMACOLOGY & THERAPEUTICS, 2000, 85 (03) :207-215
[50]   Role of gingipains R in the pathogenesis of Porphyromonas gingivalis -: Mediated periodontal disease [J].
Genco, CA ;
Potempa, J ;
Mikolajczyk-Pawlinska, J ;
Travis, J .
CLINICAL INFECTIOUS DISEASES, 1999, 28 (03) :456-465