Winners of the 2013 JA Medals for excellence

The Editorial Board of The Journal of Antibiotics has changed the terms for the JA Medal, and this prestigious award will now be presented annually to two articles, an original article and a review. The articles must have been published in the journal in the past 24 months.

The 2013 JA Medal for an original article goes to an outstanding paper entitled ‘Production of novel lipopeptide antibiotics related to A54145 by Streptomyces fradiae mutants blocked in biosynthesis of modified amino acids and assignment of lptJ, lptK and lptL gene functions’ by Dylan Alexander, Richard H Baltz and colleagues at Cubist Pharmaceuticals.¹ In this article, the authors report the mutational analysis of lipopeptide antibiotics A54145 biosynthetic genes, lptJ, lptK and lptL, revealing their molecular function and their application in the production of novel antibiotics showing potent activity even in the presence of lung surfactant.

Daptomycin is a cyclic lipopeptide that has been approved for the treatment of complicated skin and skin structure infections caused by Gram-positive bacteria, and for the treatment of bacteremia and right-sided endocarditis. However, its efficacy against community-acquired pneumonia has been insufficient for clinical use, due to the sequestration of daptomycin in the lung surfactant. Therefore, chemical modification or derivatization of daptomycin has been conducted to develop new compounds with potent activity in the presence of surfactant, but none of the compounds were active enough to carry forward into clinical studies.

A54145 is a complex of cyclic lipopeptide antibiotics related to daptomycin, produced by S. fradiae. A54145 factors contain modified amino acids, L-3-methyl-Glu₁₂ (3mGlu₁₂), L-hydroxy-Asn₃ (hAsn₃), sarcosine (Sar₅) and L-methoxy-Asp₉ (moAsp₉). The lpt gene cluster dedicated to the biosynthesis of A54245 has been cloned and analyzed, in which LptI was involved in the biosynthesis of 3mGlu₁₂. The authors constructed strains containing combinations of deletions of lptJ, ltpK and lptL genes as well as the lptI deletion. Determination of the chemical structure of their products demonstrated the molecular functions of LptJ, LptK and LptL in the amino-acid modifications, providing novel information for genome mining of cryptic secondary metabolite pathways.

The Cubist group has discovered that the antibacterial properties of A54145 can be altered by simply changing the modified amino-acid composition. Whereas the fully modified A54145E was the most active antibiotic, several compounds lacking one or two amino-acid modifications were nearly as active as A54145E in the absence of surfactant and more active in the presence of surfactant. The best compound (CB-182,390) displayed only a twofold increase in MIC over A54145E in the absence of surfactant, with no change in potency in the presence of surfactant. The success in producing unnatural natural products with unique biological activity from inactivating the various amino-acid modification enzymes described herein should help in developing a clinically useful new antibiotic.

The 2013 winner of the JA Medal for reviews is for a comprehensive and insightful overview on ‘Antibiotics in the Clinical Pipeline in 2011’ authored by Mark Butler and Matthew Cooper.² In this well-researched paper, the authors not only outline antibiotics in various stages of clinical trials, they also describe the recent history of antibiotics brought to market since 2000. The review begins with a description of the clinical need for new antibiotic drugs and of the drug discovery process, both of which are challenges that new drugs must address and negotiate. The paper presents an accurate snapshot of antibiotic discovery at this juncture: a woefully meager number of compounds in late-stage clinical trials and correspondingly very few approved drugs. This situation has not improved since publication of this review.

The current alarming state of affairs means that we have little in the pipeline to address the growing clinical need for new drugs in the short term. In other words, there are no quick fixes to the problems of resistance on the near horizon. Nevertheless, there is some room for hope, which is another message from this paper. There is a growing interest in the area of antibiotic discovery, in particular in academic and small biotech institutions, and an increasing number of compounds in Phase I and II trials and in preclinical development. The authors’ survey shows that natural product and synthetic compounds are roughly equally represented in various stages of development. While most of these are derivatives of known chemical scaffolds already in clinical use, a few are novel structures and this is encouraging. This review nicely describes the state of antibiotic development that is accessible to anyone interested in the area of antibiotic discovery and development and as such is a worthy recipient of the 2014 JA Medal for review.