Considering the rapid development of multidrug resistance to the antibiotics currently in our armamentarium, research into new agents is crucial. Multidrug resistant bacteria have become a major public health crisis because existing antibiotics are no longer effective in many cases. Antibiotics like vancomycin that have traditionally been drugs of last resort are becoming the first line of treatment of resistant infections. Unfortunately, in recent times very few novel antibiotics have been reported, and the development of new compounds by the pharmaceutical industry has been slow. Some consider that the reason for this situation is that industry is more concerned with developing drugs for chronic use in patients, instead of agents like antibiotics that are used acutely. The situation may be getting better. The Pharmaceutical Research and Manufacturing Association reports that in 2008, there are about 80 new antibiotics and antibacterial agents in various stages of development (it wasn't specified how many of these 80 agents are actually antibiotics). It is safe to assume that screening in nature for novel antibiotics is proceeding. Unfortunately, many agents that are isolated from nature are compounds that are mechanistically the same as antibiotics currently on the market.
It is essential to discover antibiotics that act through the disruption of a novel target. One success story is found in the research of scientists at Merck, who conducted high-throughput screenings of specialized metabolites against FabF, an enzyme that is involved in bacterial fatty acid biosynthesis. These screenings led to the discovery of a new antibiotic hitting a new target, platensimycin, Isolated from Streptomyces platensis cultures, platensimycin285'286 represents a new structural class of antibiotics with very potent broad-spectrum activity against Gram-positive bacteria. It is interesting that to date, no cross-resistance has been observed. This feature is probably because of platensimycin's unique mechanism of action.
In nature there are two distinct types of fatty acid biosynthesis pathways. Type 1 is referred to as the associated system, whereas type 2 is referred to as the dissociated system. Associated systems are found in higher organisms. These are composed of a large multidomain protein that is capable of catalyzing all of the steps of fatty acid biosynthesis. Dissociated systems are found in plants and bacteria. In these systems a set of discrete enzymes each catalyze a single step in the biosynthetic pathway, Hence, type 2 biosynthesis represents a good target for novel antibiotics. Moreover, two enzymes of the dissociated pathway, FabH and FabF/B, are well-conserved across many bacterial strains. This fact goes hand in hand with broad spectrum activity.
In vitro, platensimycin compares favorably with linezolid. No cross-resistance to MRSA, vancomycin-intermediate S. aureus, and vancomycin-resistant enterococci has been observed. An efflux mechanism arrears to preclude platensimycin's activity in Gram-negative bacteria.
The total synthesis of platensimycin has been reported287 and a congener, carbaplatensimycin,288 has been synthesized as well. The activity of carbaplatensimycin is similar to that of the parent platensimycin.
It is safe to assume that if any success is to be had against the rapidly developing multidrug-resistant bacteria, novel targets will have to be found. The platensimycin story is just the first case of this kind of antibiotic development.
1. Compare and contrast the mechanisms of action of the tetracyclines and the macrolides.
2. Give the correct definition of an "antibiotic."
3. Can penicillins and aminoglycosides be used synergisti-cally? If so, how?
4. What are "PBPs"? How do they work in the mechanism of action of the penicillins?
5. What is an aglycone?
6. How does spectinomycin differ from the other amino-glycoside antibiotics?
7. What bacterial genus synthesizes most of the clinically used antibiotics?
8. What are multidrug-resistant bacteria? Why are they of concern to medicine?
9. What is the unique mechanism of action of platensimycin?
10. Why do we say that cephalosporins possess "intrinsic 33-lactamase resistance"?
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