New antibiotics are necessary to treat microbial pathogens that are becoming increasingly resistant to available treatment. Despite the medical need, the number of newly approved drugs continues to decline. We offer an overview of the pipeline for new antibiotics at different stages, from compounds in clinical development to newly discovered chemical classes. Consistent with historical data, the majority of antibiotics under clinical development are natural products or derivatives thereof. However, many of them also represent improved variants of marketed compounds, with the consequent risk of being only partially effective against the prevailing resistance mechanisms. In the discovery arena, instead, compounds with promising activities have been obtained from microbial sources and from chemical modification of antibiotic classes other than those in clinical use. Furthermore, new natural product scaffolds have also been discovered by ingenious screening programs. After providing selected examples, we offer our view on the future of antibiotic discovery.

/pdf/antibiotic-discovery-in-the-twenty-first-century-current-15h6zvekf6.pdf

Antibiotic discovery in the twenty-first century: current trends and future perspectives

https://pure.hw.ac.uk/ws/files/25054354/1_s2.0_S1359511319303897_main.pdf

Sustainable microbial biosurfactants and bioemulsifiers for commercial exploitation

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 st...

http://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5b01593

Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B

Lipopeptide daptomycin is one of the few recently approved antibiotics based on the novel mechanism of action. Recent advances in synthetic lipopeptides, driven by the biochemical and biophysical research, expanded their spectrum of antimicrobial activity and reduced their size to achieve economically viable production. Lipopeptides, consisting of a short peptide chain conjugated with an acyl chain, form a structurally defined conformation, which inserts into the bacterial membrane and dissipates its transmembrane potential. In addition to antimicrobial activity, synthetic lipopeptides also suppress inflammation through the neutralization of bacterial agonists of the innate immune response, synergize with conventional antibiotics and have improved proteolytic stability. Activities in animal models indicate that synthetic lipopeptides may surpass the natural lipopeptides as the perspective class of anti-infective agents.

Synthetic lipopeptides: a novel class of anti-infectives

The discovery of nonproteinogenic amino acids among natural products, either in native state or as fragments of complex molecules, has increased the level of interest in this family of molecules from different scientific standpoints. Compounds with valuable biological properties can be found among these atypical amino acids. In addition, they have served as building blocks for the synthesis of new molecules or as surrogates of native amino acids in known peptidic entities to modulate their biological behavior. In this context, R, -diamino acids and their derivatives esters and amides, have attracted a great deal of attention among organic chemists and biochemists through the years. This interest has been due to the ubiquitous nature of R, -diamino acids as key structural fragments of biologically active compounds. Beyond this focus, the simplest compound, 2,3-diaminopropionic acid, has recently found application in the environmentally safe production of hydrogen for fuel cells, as a selective carrier of CO2 through gel membranes.1a Also, it has served to assemble a molecular device that produces propelling motion upon IR irradiation1b and, lately, in the context of food chemistry, 2,3-diaminopropionic acid has been identified as an inhibitor of polyphenol oxidase, the enzyme responsible for the browning of fruits and vegetables1c and as an enhancer of Maillard browning.1d In spite of the incidence of these molecules in an increasing number of areas, this review will deal with the biological significance, the therapeutic uses, and other interesting applications of R, -diamino acids and their derivatives found in the existing literature. Additionally, aside from the above considerations, the structural complexity of these molecules, having two vicinal chiral centers has also represented a challenge for synthetic organic chemists, especially the synthesis of enantiopure materials. Therefore, the aim of this article will also be to provide a deep and general view of the existing methodology for the synthesis of aliphatic R, or 2,3-diamino acids and their simple derivatives, esters, * To whom correspondence should be addressed. E-mail: iqov379@ iqog.csic.es. Alma Viso was born in Madrid (Spain) in 1964. She obtained a B.S. degree in Chemistry in 1987 and a Ph.D. in 1992 from Universidad Complutense de Madrid (UCM). In 1992, she moved to Massachusetts Institute of Technology (MIT) as a Fulbright fellow to work with Stephen L. Buchwald for 18 months. She joined the faculty at UCM (Madrid) in 1993 as an Assistant Professor and was promoted to Associate Professor in May 2002. In December 2002, she joined Instituto de Quı́mica Orgánica General, CSIC, as a Staff Researcher (Cientı́fico Titular) and was promoted to Senior Staff Researcher (Investigador Cientı́fico) in 2007. Her current research interests are focused in two main areas, the development of new methodologies in asymmetric synthesis using sulfoxides and sulfinamides and the application of these novel methods to efficient syntheses of therapeutically valuable products. Chem. Rev. PR1

Update 1 of: α,β-Diamino acids: biological significance and synthetic approaches.

Laspartomycin C (1), a lipopeptide antibiotic related to amphomycin, consists of a cyclic peptide core and an aspartic acid unit external to the core and linking this to a C15-2,3-unsaturated fatty acid. This was reported initially to be active against Staphylococcus aureus, and more recent studies have shown that it is active against VRE, VISA, and MRSA isolates. The enzymatic cleavage of the fatty acid tail was accomplished with a deacylase produced by Actinoplanes utahensis and resulted in two peptides, designated Peptide 1 and Peptide 2. Semisynthetic derivatives of both peptides have been made, and the principal requirement for biological activity appears to be the presence of an acylaspartic acid.

Semisynthetic approaches to laspartomycin analogues.

The present invention provides antimicrobial sulfonamide derivatives of lipopeptide antibiotics, pharmaceutical compositions of antimicrobial sulfonamide derivatives, methods for making antimicrobial sulfonamide derivatives, methods for inhibiting microbial growth with antimicrobial sulfonamide derivatives and methods for treating or preventing microbial infections in a subject with antimicrobial sulfonamide derivatives. Antimicrobial sulfonamide derivatives are generally an amino core antibiotic that has been further modified with a lipophilic sulfonyl group.

Antimicrobial sulfonamide derivatives of lipopeptide antibiotics

Disclosed herein are novel peptides and protected peptides. These compounds can be derived from naturally occurring peptides, such as those selected from colistin, circulin A, polymyxin A, polymyxin B, polymyxin D, octapeptin B, octapeptin C, and [lle7]polymyxin B1. Also disclosed are pharmaceutical compositions containing the new peptides, as well as methods for preparing the novel peptides and protected peptides.

Peptide antibiotics and methods for making same

The present invention provides laspartomycin core peptides, laspartomycin core peptide derivatives, antimicrobial laspartomycin derivatives, methods for making laspartomycin core peptides, methods for making laspartomycin core peptide derivatives, methods for making antimicrobial laspartomycin derivatives, pharmaceutical compositions of antimicrobial laspartomycin derivatives, methods of inhibiting microbial growth and methods for treating and/or preventing microbial infections in a subject.

Derivatives of laspartomycin and preparation and use thereof

Novel protected cyclopeptide intermediates are prepared from polymyxin B are used to synthesize new peptide antibiotics. Intermediates are readily derivatized and deprotected to provide new families of antibiotics, which have potent anti-bacterial activity against gram-negative bacteria; but also are useful and potent against gram-positive bacteria.

Peptide antibiotics and peptide intermediates for their prepartion

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