Reversal of the Efficacy of Beta Lactam Antibiotics Introduction Bacterial infection is one of the most threatening human health problems The death of human due to bacterial infection had exceeded than the death due to war Several researches have been conducted to treat such kind of bacterial infection since the known history The infectious bacteria are invisible to naked eye unicellular prokaryotes and different than human cells The outermost layer of the bacterial cell is composed of cell wall which is not found in mammalian human cell Therefore the cell wall can be taken as target to kill the bacteria and get rid of infection Alexander Fleming in 1928 found the clear zone rounding the colony of Penicillium notatum in the experiment of was the positive indication to get rid of such threat Nowadays almost all bacterial infection can be cured using antibiotics
The world consumes tons of antibiotics per year and half of them are beta lactam type e g amoxicillin cefixime ceftriaxome cephalexin cephalosporin monobactam carbapenem methicillin penicillin etc These beta lactam antibiotics interfere the final step in cell wall biosynthesis is transamidation reaction catalyzed by the enzyme called as penicillin binding protein PBP figure 1 which inactivates the enzyme and ultimately death of bacteria Beta lactam antibiotics have broad spectrum activity economical friendly on production good safety profile have clinical efficacy It is also target specific for prokaryotic cells cheap little side effects except some allergic reaction So it has gained wide popularity Such types of antibiotics are really useful in the context of Nepal Figure 1 Interaction of Penicillin Binding Protein PBP with β lactam Ring Nowadays it has been found that bacteria are producing beta lactamase enzyme EC 3 5 2 6 which catalyze the hydrolysis of the antibiotics i e formation of carboxyl group degrading beta lactam ring figure 2 Hydrolyzed antibiotics lose its activity or binding affinity towards the PBP Hydrolysis of beta lactam is rapid by beta lactamase than binding of beta lactam to PBP Therefore beta lactam antibiotics are becoming ineffective against these beta lactam resistant pathogenic bacteria Over 850 beta lactamases have been identified which are included into four group
A serine penicillinases B metallo β lactamases C cephalosporinases and D oxacillinases Figure 2 β Lactamase enzyme Degrading β lactam ring Two strategies have been developed to reverse the problem of resistant The first synthesis or search for beta lactamase resistant antibiotics e g penicillinase resistant beta lactam antibiotics aztreonam nafcillin oxacillin imipenem etc But if the pathogenic bacteria com in their contact these antibiotics also become susceptible to extended spectrum beta lactamase ESBL produced by multi drug resistant MDR pathogens or extreme drug resistant XDR bacteria The second approach is to use beta lactamase inhibitors coupled with beta lactam antibiotics The activity of the beta lactam containing antibiotics such as amoxicillin ampicillin piperacillin and ticarcillin can be restored These enzyme inhibitors function to permanently inactivate the beta lactamase in the periplasmic space space between cell wall and cell membrane so that the partner antibiotics can inactivate penicillin binding protein PBP Broad spectrum beta lactam antibiotics plus beta lactamase inhibitors combination have been found good safety records and clinical efficacies Augmentin is composed of amoxicillin and clavulanate in 2 1 timentin ticarcillin clavulanate tazocin piperacillin tazobactam sultamicillin ampicillin sulbactam are examples of beta lactamase inhibitors in combination with beta lactam used clinically Clavulanate exhibited clinical efficacy than others and used as standard inhibitor There is possibility to search the beta lactamase inhibiting molecule from the medicinal plant actinomycestes and other natural products as well which may reverse the inactivity of beta lactam antibiotics
Some plants such as beleric barro Terminalia bellerica Ginger aduwa Zingiber officinale waterhyssop medha giree Bacopa monnieri garlic lasun Allium sativum cowplant gudmaar Gymnema sylvestre satavari kurilo Asparagus racemosus pomegranate anar Punica granatum apple of Sodom aank Calotropis procera hina mehendi meharee Lawsonia inermis holy basil tulasi Ocimum sanctum etc has shown the beta lactamase inhibition References Bush K 1988 Beta Lactamase Inhibitors from Laboratory to Clinic Clinical Microbiology Reviews 1 1 109 123 Frère JM Joris B and Shockman GD 1984 Penicillin Sensitive Enzymes in Peptidoglycan Biosynthesis Critical Reviews in Microbiology 11 4 299 396 Marasini BP 2010 Identification of Beta lactamase Inhibitor a Strategy for Drug Development against Antibiotics Resistant Bacteria https bismar blogspot com 2010 09 identification of beta lactamse html Munoz P Garcia Garrote F and Bouza E 1996 Broad Spectrum Beta Lactam Antibiotics with Beta Lactamase Inhibitors International Journal of Antimicrobial Agents 7 S9 S14 Shaikh S et al 2014 Beta lactamase Inhibitors from Indigenous Herbs and Spices Research Journal of Pharmaceutical Biological and Chemical Sciences 5 2 275 280 Tipper DJ and Strominger JL 1965 Mechanism of Action of Penicillins A Proposal Based on Their Structural Similarity to acyl D alanyl D alanine PNAS 54 1133 1141
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