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An antibiotic must penetrate into the cell and then compete with an essential intracellular metabolite or interact with an essential bacterial macromolecule to exert its action on a bacterium. The consequence must be lethal or static interference with normal cellular function. To avoid these problems, bacteria modify their cellular permeability toward antibiotics; modify their macromolecules so that drug binding either cannot take place or so that the interaction is not fatal; modify the amount of the intracellular metabolite or their dependency upon it; or, most directly, produce enzymes that destroy the essential features of the drug.
How to overcome the Antibiotic Resistance?
The challenge of antibiotic resistance has generally been met in two ways: through the discovery of completely novel antibiotics and by the use of derivatives of known Antibiotics that are not affected by existing resistance mechanisms. An alternative to these two pathways towards new therapies as a response to antimicrobial resistance is the development of inhibitors of resistance mechanisms. In this approach, the antibiotic is co-administered with an inhibitor that neutralizes the resistance mechanism and consequently the antibiotic is still useful, even in resistant organisms. This approach has the advantage of extending the utility of antibiotics of known pharmacology, toxicology, treatments schedules and so on, long after resistance emerges.
Bacterial Resistance to Beta-lactam Antibiotics
The primary route of resistance to the Beta-lactam antibiotics is through the production of hydrolytic enzymes termed Beta-lactamases. There is well-established clinical precedent for the use of resistance inhibitors as potentiators of antibiotic action in the Beta-lactam field. Clavulanic acid, sulbactam and tazobactam are Beta-lactam compounds with only weak antimicrobial activity (Figure 1).
(Beta-lactamase enzyme inactivating beta-lactam acid "clavulanic acid")
They are, however, inhibitors of nonmetallo b-lactamases and are clinically administered in conjunction with a b-lactam antibiotic such as penicillin, amoxicillin, ampicillin or piperacillin. These inhibitory compounds act as covalent slow-dissociating inhibitors of many serine b-lactamases through acylation of the active-site serine.
Bacterial Resistance to Aminoglycosides
Resistance to the aminoglycoside antibiotics occurs primarily through regiospecific chemical modification catalyzed by O-phosphoryltransferases, N-acetyltransferases and O-adenyltransferases. The broad dissemination of these resistance mechanisms in pathogenic bacteria has limited the use of aminoglycoside antibiotics such as kanamycin, which is sensitive to all three mechanisms. Traditionally, new compounds such as tobramycin, a kanamycin analogue that lacks a key site of chemical modification (3'-hydroxyl) yet retains antimicrobial activity, have been introduced in response to the growing resistance problem.
Recently, the synthesis of 3'-oxo-aminoglycosides has been reported as means of evading the action of APH (3') kinases. In solution, the 3'-keto derivative is expected to be hydrated and therefore is a potential substrate for APH (3'). The resulting 3'-phospho-derivative is, however, unstable as a result of the ketone-diol equilibrium and the leaving group nature of the phosphate. The antibiotic is therefore readily regenerated non-enzymatically.
(Self regeneration of 3â€²-ketoaminoglycosides following phosphorylation by aminoglycoside 3â€²-kinases) The compound does not seek to inhibit resistance enzymes as a means to potentiate antibiotics; instead, this aminoglycoside is simply not affected by the presence of resistance enzymes through a bit of clever chemistry. The 3-keto derivative of kanamycin was not as effective an antibiotic as the parent compound, as assessed by its MIC (the concentration of antibiotic required to achieve complete inhibition of growth), which was 250 mg/ml versus 8 mg/ml for kanamycin. The ketone did, however, lower the MIC 4-8-fold in the presence of the resistance enzyme APH (3')-Ia. Unlike the next-generation antibiotics that seek to evade resistance by being poor substrates for existing resistance enzymes, the use of self-regenerating antibiotics such as 3'-keto-aminoglycosides could reduce the selective pressure that fuels the evolution of resistance mechanisms.
Bacterial resistance to Macrolides
Resistance to the macrolide antibiotics such as erythromycin and azithromycin occurs primarily as a result of specific base methylation of the bacterial 23S ribosomal RNA catalyzed by the Erm family of methyltransferases. After efforts has been made to discover a drug-like molecule for inhibiting the Erm methyltransferases, about 160,000 compounds have yielded nine novel chemicals that inhibited ErmC methyltransferase, five with IC50 values of < 5 µM, has been reported. Some of these compounds in combination with the macrolide antibiotic azithromycin demonstrated synergistic growth inhibition against several bacteria, demonstrating that the approach of inhibitor/antibiotic combinations is a feasible route to combat Erm-based resistance.
How does Efflux affect Resistance?
In addition to the problem of multiple resistance genes found in different organisms, certain bacteria are known to express several different efflux systems. Efflux plays an important role in resistance not only to antibacterial agents, but also to antifungal, anti-malarial and anticancer drugs as well. Membrane-bound pumps of both the multidrug resistance ABC transporter and proton-dependent major facilitator families mediate resistance by efflux. These pumps can have narrow or broad compound specificities and are widespread in bacteria. Inhibition of efflux pumps as a mechanism of potentiating antibiotic activity has been an area of vigorous research.
Examples on Compounds that inhibit resisting mechanisms or have antimicrobial activity
(4)-The natural product "4-hydroxytropolone" and derivatives were shown to be micro molar inhibitors of ANT (2'')
(6)-The dipeptide was shown to potentiate the antipseudomonal activity of the fluoroquinonlone levofloxacin.
(7)- The natural product "Reserpine" has been known for a number of years to inhibit the action of the NorA (a chromosomally encoded multidrug-resistance pump that confers resistance upon over expression) and to potentiate the action of the fluoroquinolone antibiotic norfloxacin.
(8)-Alkaloids such as "Berberine" are substrates for bacterial efflux pumps.
(9)-A screen of leaf extracts of the berberine producer Berberis fremontii resulted in the isolation of "5'methoxyhydnocarpin" a potent NorA inhibitor that potentiated the antimicrobial activity of berberine and norfloxacin. Results reveal that plants have the potential to use compound synergy to increase the potency of secondary metabolites, and alert us to the utility of natural product screens in the search for potentiators of antimicrobial activity.
The synthesis of cephalosporanic acid derivatized with hydrazine functionality at position C7b that is masked by a light sensitive o-nitrobenzyloxycarbonyl group provides a built-in light-activated 'autodestruct timer' for the inactivation of the antibiotic. Loss of the o-nitrobenzyloxycarbonyl upon exposure to light reveals the hydrazine moiety, which can now participate in an intermolecular ring expansion with the b-lactam ring, precipitating degradation of the antibiotic into non-antimicrobial byproducts. This approach provides an excellent example of the creative application of novel chemistry to reduce the selective pressure generated by the tons of antimicrobials released into the environment every year.
Role of each participant
Sarah Beshir (Typing and Organizing the Research and Writing about Antibiotic Volatility)
Mai Tarek (Writing A summary about the research and finding appropriate pictures)
Alaa Omar Sweilm (Collecting the Materials needed for the research and References)
Dina Ehab ( Summarizing Antibiotics and antibiotic resistances' definitions and efflux effect on resistance)
Dalal Galal (getting examples appropriate to the subject)
Alaa Hosni ( Writing about beta-lactam and marcolides resistance)
Nada Hussien ( Writing about Aminoglycoside resistance)