Novel Drugs Target Tough-to-Treat Bacteria

 

Published: Sep 9, 2014

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WASHINGTON - Researchers described early progress in the development of new agents that target difficult-to-treat Gram-negative resistant bacteria, including one drug already in early human testing that uses a "Trojan Horse" concept.

In preclinical testing in a mouse model, the parenteral siderophore cephalosporin named S-649266 showed in vitro and in vivo effectiveness in killing multidrug-resistant Pseudomonas and Acinetobacter species, and carbapenem-resistant Enterobacteriaceae in rodent models of thigh and lung infections, reported Yoshinori Yamano, PhD, vice president of medical research laboratories at Shionogi and Co., based in Osaka, Japan.

Also, in testing among healthy volunteers, 54 individuals were able to tolerate up to 2 g of S-649266, reported Yutaka Saisho, a researcher with Shionogi, at the Interscience Conference on Antimicrobial Agents and Chemotherapy. One of the volunteers had to withdraw from the study due to adverse thyroid tests, but there were no serious adverse events.

As a result of these positive results, the company had begun phase II studies of the drug, said Tsutae Den Nagata, MD PhD, chief medical officer for Shionogi.

Yamano described how the "Trojan Horse" effect allows S-694266 to get into the cell where it can kill the drug-resistant organism.

Gram-negative bacteria acquire iron which is necessary for growth and multiplication, and S-649266 binds to iron. When Gram-negative bacteria acquire iron bound to S-649266, they also absorb S-649266, transporting the drug through the outer membrane into the periplasmic space where it binds to penicillin-binding proteins and disrupts cell wall synthesis, he explained.

This use of the iron uptake system may allow S-649266 to be an effective approach to treat Gram-negative bacterial infections that are not able to be treated by available antibiotics, the researchers said.

"These studies target ... the most important problem in hospitals today, and that is the multidrug-resistant Gram-negative organisms," commented Richard Wenzel, MD, professor and chairman of internal medicine at the Virginia Commonwealth University Medical Center in Richmond.

"Clinicians are very comfortable using cephalosporins," he explained to MedPage Today. "With years of use of the carbapenems, the organisms - which are much smarter than we are -- have built up resistance, so we have very few drugs to treat carbapenem-resistant rods. Two years ago we had no drugs in the pipeline to treat these metallo-beta-lactamases and none for multidrug-resistant Pseudomonas, so if I sound excited it is because clinically we really haven't had anything, and here is a promising drug."

S-649266 was one of several drugs featured in an ICAAC symposium dedicated to new treatments in the development pipeline. Other drugs highlighted were:

• AA139 targets the outer membrane of Gram-negatives such as Pseudomonas aeruginosa (Adenium Biotech).
• ASP2397 has potent fungicidal activity against Aspergillus (Astellas Pharma).
• TD-1607 is a glycoprotein-cephalosporin for multidrug-resistant Gram-positive infections (Theravance Biopharma).
• OP0595 is a new series beta-lactamase inhibitor (Meiji Seika Pharma).

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Primary source: Interscience Conference on Antimicrobial Agents and Chemotherapy
Source reference: Saisho Y, et al "S-694266, a novel siderophore cephalosporin for gram negative bacterial infections: Pharmacokinetics, safety and tolerability in healthy subjects" ICAAC 2014; Abstract F-1564.

Additional source: Interscience Conference on Antimicrobial Agents and Chemotherapy
Source reference:Yamano Y, et al "A parenteral siderophore cephalosporin S-649266 active against MDR Gram-negative pathogens" ICAAC 2014.