Discovery of functionally selective C5aR2 ligands: novel modulators of C5a signalling.

The complement cascade is comprised of a highly sophisticated network of innate immune proteins that are activated in response to invading pathogens or tissue injury. The complement activation peptide, C5a, binds two seven transmembrane receptors, namely the C5a receptor 1 (C5aR1) and C5a receptor 2 (C5aR2, or C5L2). C5aR2 is a non-G-protein-signalling receptor whose biological role remains controversial. Some of this controversy arises owing to the lack of selective ligands for C5aR2. In this study, a library of 61 peptides based on the C-terminus of C5a was assayed for the ability to selectively modulate C5aR2 function. Two ligands (P32 and P59) were identified as functionally selective C5aR2 ligands, exhibiting selective recruitment of ß-arrestin 2 via C5aR2, partial inhibition of C5a-induced ERK1/2 activation and lipopolysaccharide-stimulated interleukin-6 release from human monocyte-derived macrophages. Importantly, neither ligand could induce ERK1/2 activation or inhibit C5a-induced ERK1/2 activation via C5aR1 directly. Finally, P32 inhibited C5a-mediated neutrophil mobilisation in wild-type, but not C5aR2(-/-) mice. These functionally selective ligands for C5aR2 are novel tools that can selectively modulate C5a activity in vitro and in vivo, and thus will be valuable tools to interrogate C5aR2 function.

Antibiotics in the clinical pipeline at the end of 2015.

There is growing global recognition that the continued emergence of multidrug-resistant bacteria poses a serious threat to human health. Action plans released by the World Health Organization and governments of the UK and USA in particular recognize that discovering new antibiotics, particularly those with new modes of action, is one essential element required to avert future catastrophic pandemics. This review lists the 30 antibiotics and two ß-lactamase/ß-lactam combinations first launched since 2000, and analyzes in depth seven new antibiotics and two new ß-lactam/ß-lactamase inhibitor combinations launched since 2013. The development status, mode of action, spectra of activity and genesis (natural product, natural product-derived, synthetic or protein/mammalian peptide) of the 37 compounds and six ß-lactamase/ß-lactam combinations being evaluated in clinical trials between 2013 and 2015 are discussed. Compounds discontinued from clinical development since 2013 and new antibacterial pharmacophores are also reviewed.

Institutional profile: Community for Open Antimicrobial Drug Discovery - crowdsourcing new antibiotics and antifungals.

The Community for Open Antimicrobial Drug Discovery (CO-ADD) is a not-for-profit, collaborative approach to discovering new antibiotics. We access novel chemical diversity from academic synthetic chemists, who collectively possess millions of untested compounds with chemical diversity that lie outside commercial collections. We perform high-throughput antimicrobial screening of pure compounds derived from both synthetic and natural sources free of charge. The resulting data can be used by participants for publication, patenting and development purposes, and is fed back into the research community through an open-access database after a 2-year period during which information is kept confidential to the provider. CO-ADD is fundamentally asking two questions: can the community work together to address the global threat of antimicrobial resistance; and are there as yet undiscovered, novel antimicrobial compounds already present within our diverse global chemistry community?

Old dogs and new tricks in antimicrobial discovery.

The discovery of new antibiotics is crucial if we are to avoid a future in which simple infections once again lead to death. New antibiotics were traditionally discovered by analyzing extracts from cultured soil-derived microbes. However, in the last few years only a few new antibiotic classes have been identified using this method. Attempts to apply target-based screening approaches to antibiotic discovery have also proven to be unproductive. In this article, we describe how DNA sequencing and bioinformatic techniques are revolutionizing natural product discovery leading to new natural product antibiotics sourced from both cultivated and uncultivated microbes. New chemical structures are also being 'crowd sourced' from chemists around the world, and 'forgotten' antibiotics repositioned for clinical trials after chemical or biochemical modification of the original natural product. Collectively such approaches have the potential to revamp antibiotic lead discovery and re-invigorate the antibiotic pipeline.