Mark A. T. Blaskovich

Glycopeptide antibiotics: back to the future

Glycopeptide antibiotics have been a key weapon in the fight against bacterial infections for over half a century, with the progenitors, vancomycin (1) and teicoplanin (2), still used extensively. The increased occurrence of resistance and the effectiveness of these ‘last resort’ treatments for Gram-positive infections has led to the discovery and clinical development of second generation, semisynthetic lipoglycopeptide derivatives such as telavancin (3), dalbavancin (4) and oritavancin (5), which all possess broader spectra of activity and improved pharmacokinetic properties. Two of these new antibiotics, telavancin (3) and dalbavancin (4), were approved in the past 5 years and the third, oritavancin (5), is awaiting regulatory approval. In this review, the discovery, development and associated resistance of vancomycin (1) and teicoplanin (2), and semi-synthetic glycopeptides, telavancin (3), dalbavancin (4) and oritavancin (5), are detailed. The clinical implications of glycopeptide resistance, especially vancomycin (1), as well as the future prospects for current glycopeptide drugs and the development of new glycopeptides are discussed.

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 β-lactamase/β-lactam combinations first launched since 2000, and analyzes in depth seven new antibiotics and two new β-lactam/β-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 β-lactamase/β-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.

Recent discovery and development of protein tyrosine phosphatase inhibitors

The protein tyrosine phosphatases (PTPases or PTPs) play an important role in controlling the status of tyrosine phosphorylation and the regulation of cellular function. The ability to selectively inhibit PTPs holds enormous therapeutic potential for the treatment of diseases such as diabetes, cancer and osteoporosis. However, an understanding of the role of many PTPs has yet to be unravelled, with only PTP1B convincingly validated as a therapeutic target. Furthermore, the intricate network of different PTPs extensively involved in signalling events requires high selectivity for the desired PTP target, in order to minimise potential side effects. Most research programmes into PTP inhibitors are still at an early stage and have yet to convert initial leads into compounds with more drug-like properties. Inhibitors have been identified by modification of peptide substrates, from natural product screening and by rational design. This article will give an overview of PTPs, followed by a more detailed description of the development of PTP inhibitors. Patents on PTP inhibitors published between January 1998 and Feb 2002 will be discussed in the context of the available literature.

Clostridium difficile drug pipeline: challenges in discovery and development of new agents.

In the past decade Clostridium difficile has become a bacterial pathogen of global significance. Epidemic strains have spread throughout hospitals, while community acquired infections and other sources ensure a constant inoculation of spores into hospitals. In response to the increasing medical burden, a new C. difficile antibiotic, fidaxomicin, was approved in 2011 for the treatment of C. difficile-associated diarrhea. Rudimentary fecal transplants are also being trialed as effective treatments. Despite these advances, therapies that are more effective against C. difficile spores and less damaging to the resident gastrointestinal microbiome and that reduce recurrent disease are still desperately needed. However, bringing a new treatment for C. difficile infection to market involves particular challenges. This review covers the current drug discovery pipeline, including both small molecule and biologic therapies, and highlights the challenges associated with in vitro and in vivo models of C. difficile infection for drug screening and lead optimization.

Highly efficient and versatile synthesis of libraries of constrained β-strand mimetics

The general approach of using a bicyclic template to produce inhibitors of the protease superfamily of enzymes has been investigated. The Diels-Alder cycloaddition reaction on solid support has been found to be highly efficient for the synthesis of libraries of compounds that mimic the β-strand secondary structure of proteins. Several potent and selective inhibitors of proteases have been discovered.

Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B

The polymyxin lipodecapeptides colistin and polymyxin B have become last resort therapies for infections caused by highly drug-resistant Gram-negative bacteria. Unfortunately, their utility is compromised by significant nephrotoxicity and polymyxin-resistant bacterial strains. We have conducted a systematic activity–toxicity investigation by varying eight of the nine polymyxin amino acid free side chains, preparing over 30 analogues using a novel solid-phase synthetic route. Compounds were tested against a panel of Gram-negative bacteria and counter-screened for in vitro cell toxicity. Promising compounds underwent additional testing against primary kidney cells isolated from human kidneys to better predict their nephrotoxic potential. Many of the new compounds possessed equal or better antimicrobial potency compared to polymyxin B, and some were less toxic than polymyxin B and colistin against mammalian HepG2 cells and human primary kidney cells. These initial structure–activity and structure–toxicity studies set the stage for further improvements to the polymyxin class of antibiotics.

Unusual Amino Acids in Medicinal Chemistry

Unusual amino acids are fundamental building blocks of modern medicinal chemistry. The combination of readily functionalized amine and carboxyl groups attached to a chiral central core along with one or two potentially diverse side chains provides a unique three-dimensional structure with a high degree of functionality. This makes them invaluable as starting materials for syntheses of complex molecules, highly diverse elements for SAR campaigns, integral components of peptidomimetic drugs, and potential drugs on their own. This Perspective highlights the diversity of unnatural amino acid structures found in hit-to-lead and lead optimization campaigns and clinical stage and approved drugs, reflecting their increasingly important role in medicinal chemistry.

Cell- and biomarker-based assays for predicting nephrotoxicity

Introduction: Drug-induced nephrotoxicity contributes to the failure rate of investigational drugs during clinical trials. We are still not able to accurately predict drug-induced nephrotoxicity during early drug discovery and development. There is an urgent need for a robust screening system that can identify nephrotoxic compounds before they reach the clinic. Areas covered: This review discusses traditional and emerging kidney injury biomarkers that are used for the determination of nephrotoxicity and for evaluation and diagnosis of other kidney diseases. The potential for in vivo biomarkers to predict renal toxicity in high-throughput in vitro screening assays is discussed. We also compare cell types and highlight novel three-dimensional (3D) culture technologies with potential for in vitro prediction of nephrotoxicity. Expert opinion: Traditional cell culture methods and cytotoxicity assays are well established as in vitro tests for nephrotoxicity but the correlation with in vivo results is extremely poor. Recently validated renal biomarkers show promise for early in vivo detection of nephrotoxicity, but have yet to be successfully applied for in vitro prediction of drug-induced nephrotoxicity. Advanced culture technologies ‘kidney-on-a-chip’ and 3D culture can produce biomarker signatures from relevant kidney cell types that show promise as better predictive systems.

Antibacterial serrulatane diterpenes from the Australian native plant Eremophila microtheca

Chemical investigations of the aerial parts of the Australian plant Eremophila microtheca resulted in the isolation of three serrulatane diterpenoids, 3-acetoxy-7,8-dihydroxyserrulat-14-en-19-oic acid (1), 3,7,8-trihydroxyserrulat-14-en-19-oic acid (2) and 3,19-diacetoxy-8-hydroxyserrulat-14-ene (3) as well as the previously reported compounds verbascoside (4) and jaceosidin (5). Acetylation and methylation of the major serrulatane diterpenoid 2 afforded 3,8-diacetoxy-7-hydroxyserrulat-14-en-19-oic acid (6) and 3,7,8-trihydroxyserrulat-14-en-19-oic acid methyl ester (7), respectively. The antibacterial activity of 1-7 was assessed against a panel of Gram-positive and Gram-negative bacterial isolates. All of the serrulatane compounds exhibited moderate activity against Streptococcus pyogenes (ATCC 12344) with minimum inhibitory concentrations (MICs) ranging from 64-128 μg/mL. Serrulatane 1 demonstrated activity against all Gram-positive bacterial strains (MICs 64-128 μg/mL) except for Enterococcus faecalis and Enterococcus faecium. This is the first report of natural products from E. microtheca.

Evaluation of biomarkers for in vitro prediction of drug- induced nephrotoxicity: comparison of HK-2, immortalized human proximal tubule epithelial, and primary cultures of human proximal tubular cells

There has been intensive effort to identify in vivo biomarkers that can be used to monitor drug‐induced kidney damage and identify injury before significant impairment occurs. Kidney injury molecule‐1 (KIM‐1), neutrophil gelatinase‐associated lipocalin (NGAL), and human macrophage colony stimulating factor (M‐CSF) have been validated as urinary and plasma clinical biomarkers predictive of acute and chronic kidney injury and disease. Similar validation of a high throughput in vitro assay predictive of nephrotoxicity could potentially be implemented early in drug discovery lead optimization to reduce attrition at later stages of drug development. To assess these known in vivo biomarkers for their potential for in vitro screening of drug‐induced nephrotoxicity, we selected a panel of nephrotoxic agents and examined their effects on the overexpression of nephrotoxicity biomarkers in immortalized (HK‐2) and primary (commercially available and freshly in‐house produced) human renal proximal tubule epithelial cells. Traditional cytotoxicity was contrasted with expression levels of KIM‐1, NGAL, and M‐CSF assessed using ELISA and real‐time quantitative reverse transcription PCR. Traditional cytotoxicity assays and biomarker assays using HK‐2 cells were both unsuitable for prediction of nephrotoxicity. However, increases in protein levels of KIM‐1 and NGAL in primary cells were well correlated with dose levels of known nephrotoxic compounds, with limited correlation seen in M‐CSF protein and mRNA levels. These results suggest that profiling compounds against primary cells with monitoring of biomarker protein levels may have potential as in vitro predictive assays of drug‐induced nephrotoxicity.