Cryptic antibiotic genes

Question

What are cryptic antibiotic genes or what is cryptic antibiotic resistance, and what makes it "cryptic"?

Answer 1

I suggest reading Phylogenetic Trees Made Easy.

Big pharma gave up on soil bacteria as a source of antibiotics too soon, according to research published in the June issue of Microbiology. "Over the last eight years we have been looking for new natural products in the DNA sequence of the antibiotic-producing bacterium Streptomyces coelicolor," said Professor Gregory Challis from the University of Warwick.

In 1928 Alexander Fleming discovered penicillin, which was subsequently developed into a medicine by Florey and Chain in the 1940s. Currently the complete genetic sequences of more than 580 microbes are known. Professor Challis and his colleagues have discovered the products of two cryptic gene clusters.

The other product they discovered is called coelichelin. Many researchers have followed Professor Challis and his colleagues into the exciting field of genome mining. Scientists have been mining microbial genomes for new natural products that may have applications in the treatment of MRSA and cancer and have made some exciting discoveries. In the last 15 years it became accepted that no new natural products remained to be discovered from these bacteria. Our work shows this widely-held view to be incorrect."

The antibiotic was hailed as a 'miracle cure' and a golden age of drug discovery followed. However, frequent rediscovery of known natural products and technical challenges forced pharmaceutical companies to retreat and stop looking for new molecules. It is possible to identify pathways that produce new compounds by looking at the DNA sequences and many gene clusters likely to encode natural products have been analysed. 'Genome mining' has become a dynamic and rapidly advancing field. One of the clusters was found to produce several compounds that inhibit the proliferation of certain bacteria.

The resistome is a proposed expression by Gerard D. Wright for the collection of all the antibiotic resistance genes and their precursors both in pathogenic and non-pathogenic bacteria. Resistance genes found on pathogenic bacteria. These are the fewest but also the most problematic ones at present. Resistance genes found on antibiotic producers. The microorganisms such as soil-dwelling bacteria and fungi that naturally produce antibiotics have their own protection mechanisms to avoid the adverse effects of the antibiotics on them selfs. The genes which code for these resistances are a strong source for the pathogenic bacteria.

Three of these compounds were new ones, named isogermicidin A, B and C. "This discovery was quite unexpected," said Professor Challis. "Our research provides important new methodology for the discovery of new natural products with applications in medicine, such as combating MRSA infections." Although it is the fourth most abundant element in the Earth's crust it often exists in a ferric form, which microbes are unable to use. "The gene cluster that directs production of coelicehlin was not known to be involved in the production of any known products," said Professor Challis. "Our research suggests that coelichelin helps S. coelicolor take up iron." "In the near future, compounds with useful biological activities will be patented and progressed into clinical or agricultural trials, depending on their applications" said Professor Challis.

Researchers at the University of Rochester have developed two breakthrough tools to be used in the fight against antibiotic resistance. Both tools have been featured in the May 2004 issue of Nature Reviews Microbiology and one is the subject of a recently issued U.S. patent. The first tool, the Barlow-Hall In-Vitro Evolution Method (U.S. Patent 6,720,142), accurately predicts in a laboratory how antibiotic resistance, which is caused by special "resistance genes," will naturally evolve to resist antibiotic drugs. The second tool, GeneHunter (patent application pending), is a method that can identify unknown resistance genes. GeneHunter can be used to screen bacteria for the presence of "silent," or cryptic, genes that may also increase antibiotic resistance. As reported in the May 2004 issue of Nature Reviews Microbiology, the "...global antibiotic market is now estimated at more than U.S. $25 billion annually." Yet, many drugs in that market are increasingly ineffective at controlling bacterial infections because some bacteria have evolved to become resistant to these drugs.

The evolution of antibiotic resistance in bacteria is a topic of major medical importance. Evolution is the result of natural selection acting on variant phenotypes. Both the rigid base sequence of DNA and the more plastic expression patterns of the genes present define phenotype. We investigated the evolution of resistant E. coli when exposed to low concentrations of antibiotic. We show that within an isogenic population there are heritable variations in gene expression patterns, providing phenotypic diversity for antibiotic selection to act on. We studied resistance to three different antibiotics, ampicillin, tetracycline and nalidixic acid, which act by inhibiting cell wall synthesis, protein synthesis and DNA synthesis, respectively. In each case survival rates were too high to be accounted for by spontaneous DNA mutation. In addition, resistance levels could be ramped higher by successive exposures to increasing antibiotic concentrations. Furthermore, reversion rates to antibiotic sensitivity were extremely high, generally over 50%, consistent with an epigenetic inheritance mode of resistance.