Kosan K-1325, a new ketolide

Topics with information and discussion about published studies related to Lyme disease and other tick-borne diseases.
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Joe Ham
Posts: 489
Joined: Fri 27 Jul 2007 6:15
Location: New Mexico, USA

Kosan K-1325, a new ketolide

Post by Joe Ham » Sat 21 Mar 2009 16:17

Kosan Biosciences Inc, Hayward, Calif. the developer of this new Ketolide was sold to Bristol-Myers Squibb last year. No trials of this drug are underway yet.
Antimicrobial Agents and Chemotherapy, April 2009, p. 1411-1419, Vol. 53, No. 4

Distinct Mode of Interaction of a Novel Ketolide Antibiotic That Displays Enhanced Antimicrobial Activity
http://aac.asm.org/cgi/content/full/53/4/1411

Ekaterini C. Kouvela,1 Dimitrios L. Kalpaxis,1 Daniel N. Wilson,2 and George P. Dinos1*
Laboratory of Biochemistry, School of Medicine, University of Patras, 26500 Patras, Greece,1 Center for Integrated Protein Science Munich CiPSM, and Gene Center and Department of Chemistry and Biochemistry, Ludwig-Maximilians-Universität Munchen, Feodor-Lynen-Strasse 25, D-81377 Munich, Germany2

ABSTRACT

Ketolides represent the latest generation of macrolide antibiotics, displaying improved activities against some erythromycin-resistant strains, while maintaining their activity against erythromycin-susceptible ones. In this study, we present a new ketolide, K-1325, that carries an alkyl-aryl side chain at C-13 of the lactone ring. According to our genetic and biochemical studies, K-1325 binds within the nascent polypeptide exit tunnel, at a site previously described as the primary attachment site of all macrolide antibiotics. Compared with telithromycin, K-1325 displays enhanced antimicrobial activity against wild-type Escherichia coli strains, as well as against strains bearing the U2609C mutation in 23S rRNA. Chemical protection experiments showed that the alkyl-aryl side chain of K-1325 interacts specifically with helix 35 of 23S rRNA, a fact leading to an increased affinity of U2609C mutant ribosomes for the drug and rationalizing the enhanced effectiveness of this new ketolide.


INTRODUCTION

The macrolide class of antibiotics represents a large family of protein synthesis inhibitors that has received a lot of attention because many are already used in human medicine (17, 24). Each family member is characterized by the presence of a lactone ring to which distinctive side chain residues are attached. Erythromycin (Fig. 1) was the first member of the macrolide family introduced into therapeutic use, followed by clarithromycin and azithromycin (Fig. 1) (17). Structural studies have revealed that all of the above-mentioned macrolides bind within a hydrophobic crevice of the nascent polypeptide exit tunnel (3, 13, 31, 37), consistent with the long-standing view that macrolides act by hindering the progression of the nascent peptide chain through the ribosomal tunnel, which eventually leads to peptidyl-tRNA "drop-off" (19, 20).
The rapid and sudden increase in macrolide resistance in the 1980s and 1990s (29) led to the development of improved compounds, termed ketolides (1, 22).

cave76
Posts: 3182
Joined: Sun 12 Aug 2007 2:27

Re: Kosan K-1325, a new ketolide

Post by cave76 » Sat 21 Mar 2009 17:04

Many abstracts about macrolides can be found simply by going to:

http://www.ncbi.nlm.nih.gov/sites/entrez/

..... and typing in the words macrolides AND new

One of them :

Anaerobe. 2009 Mar 14. [Epub ahead of print]Click here to read Links
Antimicrobial susceptibility of anaerobic bacteria in bulgaria.
Marina M, K Ivanova M, Kantardjiev T.

Anaerobic Laboratory, Department of Microbiology, National Center of Infectious and Parasitic Diseases, Sofia, Bulgaria.

OBJECTIVES: The antimicrobial susceptibility of anaerobic bacteria isolated from clinical specimens in the referent for Bulgaria anaerobic laboratory was studied in a period of 25 years /1983-2007/. METHODS: NCCLS - recommended agar dilution methods were used. beta-lactamase activity was determined with nitrocefin discs. RESULTS: The 29 antimicrobial agents included in the study were divided according to their in vitro activity against the anaerobic isolates into 4 main groups for guiding empirical treatment: 1(st) group of metronidazole, chloramphenicol, meropenem, imipenem and combinations of beta-lactam antibiotics with sulbactam - with high activity and drugs of choice for treatment; 2(nd) group - clindamycin, cefoxitin, carbenicillin /and azlocillin, piperacillin/ - with a good activity and low percent of resistant strains; 3(rd) group - of tetracycline and erythromycin with higher percent of resistant strains including the new macrolides as josamycin, clarithromycin, roxithromycin and azithromycin; 4(th) group - penicillins /ampicillin, amoxicillin, penicillin/ and cephalosporins /cefamandole, cefazolin, cefotaxime and cefoperazone/ - not suitable for treatment of infections including Bacteroides fragilis group strains, with a very high percent of resistant strains, probably due to beta-lactamase activity in most of the strains. CONCLUSION: A continued updating and a follow-up in the changes of antibiotic susceptibility is necessary in every country as resistance patterns vary not only between geographical regions but even among medical centers and hospitals which may be connected with differences in antibiotic usage in man and animals.

PMID: 19292999 [PubMed - as supplied by publisher]

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The use of PubMed to find articles suitable for the Science forum here is easy.

Although the Boolean modifiers are necessary for 'refined' searches I find, that for simple searches the modifiers AND and NOT can filter out some of the abstracts (like those for veterinary uses) by

macrolide AND new NOT veterinary.

Here is the url for the Help/Faq page at PubMed. Don't get bogged down by all the 'help'. Just the top few will produce quite a bit.

Try it, you'll like it. And you won't have to wait for someone to post an abstract here.

Joe Ham
Posts: 489
Joined: Fri 27 Jul 2007 6:15
Location: New Mexico, USA

Re: Kosan K-1325, a new ketolide

Post by Joe Ham » Sat 21 Mar 2009 17:51

This is the url for PubMed search:
http://www.ncbi.nlm.nih.gov/sites/entre ... &db=pubmed

Google Scholar is also productive:
http://scholar.google.com/

cave76
Posts: 3182
Joined: Sun 12 Aug 2007 2:27

Re: Kosan K-1325, a new ketolide

Post by cave76 » Sat 21 Mar 2009 18:23

Yes, they all work.

Fin24
Posts: 1699
Joined: Sat 8 Mar 2008 20:14

Re: Kosan K-1325, a new ketolide

Post by Fin24 » Sat 21 Mar 2009 20:00

is the new keto as risky as Ketek??

that was a quick back off once many were harmed

cave76
Posts: 3182
Joined: Sun 12 Aug 2007 2:27

Re: Kosan K-1325, a new ketolide

Post by cave76 » Sat 21 Mar 2009 20:27

****is the new keto as risky as Ketek??

that was a quick back off once many were harmed*****

That's why I tend to stick with the older abx.
The newer ones are getting too quick a 'pass' due to wanting to get to market too soon.

I have no 'proof' of newer abx always being risky. Just reading and watching the forums as an avocation (not believing or disbelieving, just taking notes) can sometimes teach more than a zillion abstracts---- as important as they are to researchers.

Remember, each abstract is just a snapshot in time.

"This Little Piggie Went to Market"

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