所选译文位置：《制药工程专业英语》Unit9，P96-98 外文文献原稿和译文
原 稿
Throughout recorded history ，bacterial infections have periodically exacted heavy tolls on the human population .During “Black Death”bubonic plague episode of 1347-1351.Yersinia pestis killed an estimated 25 million in Asia and Europe .US Public上海南洋电机
Heath Service statistics for 1910 and 1920 show that early in this century tuberculosis killed one in every 1000 US residents . Even today ,mainly in developing countries ,Mycobacterium tuberculosis remains the leading cause of death attributable to a single infectious agent, killing over three million people worldwide every year.
Within just a few decades, the availability of an anti-infective pharmacopoeia suddenl
y provided humans with the potential to circumvent Nature's time-tested, live-or-die evolutionary paradigm for enhancing their survival prospects under constant microbial barrage. Those members that previously would have succumbed could now survive longer with the help of vaccines and antibiotics - auxiliary agents which work alongside the immune system to fight infection. In effect, humans' employment of these auxiliaries can be looked upon as exemplifying a self-contrived evolution in their immunological defense system. ADAU1452
Once the usefulness of Sir Alexander Fleming's penicillin discovery had been demonstrated, a flurry of other antibiotics unearthed from natural sources followed. Some of these proved suitable for treating disease, usually after chemical modification to improve the natural compound's potency, safety or pharmacokinetic profiles.
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For most of the past 50 years, it seemed that medical science had gained a strong upper hand over bacterial disease. Some pharmaceutical houses and funding agen
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cies decided to cut back on antibiotic discovery efforts, as it appeared that the physician's antibacterial arsenal was well stocked. But the nature of the diseases has proved otherwise.
The rapid escalation in the incidence of multiple-antibiotic-resistant pathogens is now raising very serious concerns worldwide.This development underscores the powerful evolutionary capabilities of bacterial populations under the selective pressure imposed by antibiotic therapy .
Antibiotic resistance Resistance problems are seen with both Gram-negative(for example Escherichia coli) and Gram-positive bacteria (such as Staphylococcus aureus), but most of the concerns are with the latter group of pathogens.Streptococcus is a respiratory Gram-positive pathogen responsible for 40,000 deaths a year in the US alone. A rapidly rising prevalence of penicillin-resistant S. pneumoniae infections is now problematic in many countries. One of the worst situations is in Hungary, where 70%of the S. from children tested in 1988-1989 were resistant to penicillin.
Bacteria have evolved numerous ploys for defeatng antibiotic action——they inactivate the antibiotic by hydrolysis, acylation , phosphorylation or nucleotidylation reactions; aitre the antibiotic’s target site; or reduce the intracellular drug concentration by decreasing membrane permeability and/or actively pumping the drug out of the cell . With improved understanding of these mechanisms of resistance through molecular biology and biochemical techniques, medicinal chenmists have been provided with the targets for attempting to circumvent some of the resistance problems.
snow dogsA predominant resistance mechanism against the B-lactam drugs (such as Penicillin) involves enzymatic cleavage of the B-lactam ring. While the drug Methicillin was developed because it could withstand such action, strains of Methicillin-resistance S.ayreus (MRSA) emerged in 1961 , jusr two years after the drug first went into wide use . MRSA strains evolved so that they had an additional drug-target protein involved with cell wall biosynthesis, and this altered protein has a very low affinity for virtually all B-lactams. To make matters worse, mose MR
SA strains are also resistant to many other classes of antibiotics,with the exception of the glycopeptide Vancomycin. Now seen around the globe, MRSA strains are very problematic in Japan ( where in some hospitials 60% of S. Aureus isolates are MRSA ), as well as in Spain , France , Italy and the US , each with a greater than 30% incidence.
A particularly disturbing milestone was the 1988 emergence of Vancomycin-resistant enterococci (VRE). Some VRE now don’t respond to any available antibiotics. The enterococci have become the second mose frequently encountered hospital acquired pathogne in the US, where the incidence of VRE strains is now about 15% of all clinical enterococcal isolates . Resistance to Vancomycin arises because a D-alanine-D-lactate residue ( which vancomycin binds to only poorly) has been substituted for the D-alanine-D-alanine residue normally found at the rerminus of a pentapeptide precursor involved in the bacteria’s cell wall biosynthesis.
There is now a great concern that the genes conferring resistance in VRE to glycopeptides like Vancomycin will be naturally transferred to S.aureus, has been experimentally demonstrated feasible by William Noble at St Thomas' Hospital, London. As Vancomycin is the drug of last resort for treating MRSA infections, the anticipated natural acquisition of Vancomycin resistance in this virulent pathogen would result in the sobering return to pre-antibiotic era therapeutic failures, should no alternate effective therapy become available.
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