Antibiotics: the molecular marvels of modern medicine

Inaugural speech delivered by Prof.dr. Nathaniel I. Martin at the acceptance of professor Biological Chemistry at the Faculty of Sciences at Leiden University on September 13. 2019.Microbial Biotechnolog

Synergy by perturbing the gram-negative outer membrane: opening the door for gram-positive specific antibiotics

New approaches to target antibacterial agents toward Gram -negative bacteria are key, given the rise of antibiotic resistance. Since the discovery of polymyxin B nonapeptide as a potent Gram-negative outer membrane (OM)-permeabilizing synergist in the early 1980s, a vast amount of literature on such synergists has been published. This Review addresses a range of peptide-based and small organic compounds that disrupt the OM to elicit a synergistic effect with antibiotics that are otherwise inactive toward Gram -negative bacteria, with synergy defined as a fractional inhibitory concentration index (FICI) of <0.5. Another requirement for the inclusion of the synergists here covered is their potentiation of a specific set of clinically used antibiotics: erythromycin, rifampicin, novobiocin, or vancomycin. In addition, we have focused on those synergists with reported activity against Gram-negative members of the ESKAPE family of pathogens namely, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and/or Acinetobacter baumannii. In cases where the FICI values were not directly reported in the primary literature but could be calculated from the published data, we have done so, allowing for more direct comparison of potency with other synergists. We also address the hemolytic activity of the various OM-disrupting synergists reported in the literature, an effect that is often downplayed but is of key importance in assessing the selectivity of such compounds for Gram-negative bacteria.Microbial Biotechnolog

Thiol-Containing Metallo-β-Lactamase Inhibitors Resensitize Resistant Gram-Negative Bacteria to Meropenem

Microbial Biotechnolog

The contribution of achiral residues in the laspartomycin family of calcium-dependent lipopeptide antibiotics

The growing threat of antibacterial resistance is a global concern. The so-called calcium-dependent lipopeptide antibiotics (CDAs) have emerged as a promising source of new antibiotic agents that are rich in structural and mechanistic diversity. Over forty unique CDAs have been identified to date and share a number of common features. Recent efforts in our group have provided new mechanistic and structural insights into the laspartomycin family of CDAs. We here describe investigations aimed at probing the role of the three glycine residues found in the laspartomycin peptide macrocycle. In doing so laspartomycin analogues containing the achiral 2-aminoisobutyric acid (AIB) as well as L- or D-alanine in place of glycine were prepared and their antibacterial activities evaluated.Microbial Biotechnolog

Nicotinamide N-Methyl Transferase (NNMT): an emerging therapeutic target

Microbial Biotechnolog

Recent advances in the development of semisynthetic glycopeptide antibiotics: 2014–2022

The accelerated appearance of drug-resistant bacteria poses an ever-growing threat to modern medicine's capacity to fight infectious diseases. Gram-positive species such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae continue to contribute significantly to the global burden of antimicrobial resistance. For decades, the treatment of serious Gram-positive infections relied upon the glycopeptide family of antibiotics, typified by vancomycin, as a last line of defense. With the emergence of vancomycin resistance, the semisynthetic glycopeptides telavancin, dalbavancin, and oritavancin were developed. The clinical use of these compounds is somewhat limited due to toxicity concerns and their unusual pharmacokinetics, highlighting the importance of developing next-generation semisynthetic glycopeptides with enhanced antibacterial activities and improved safety profiles. This Review provides an updated overview of recent advancements made in the development of novel semisynthetic glycopeptides, spanning the period from 2014 to today. A wide range of approaches are covered, encompassing innovative strategies that have delivered semisynthetic glycopeptides with potent activities against Gram-positive bacteria, including drug-resistant strains. We also address recent efforts aimed at developing targeted therapies and advances made in extending the activity of the glycopeptides toward Gram-negative organisms.Microbial Biotechnolog

Polymyxin stereochemistry and its role in antibacterial activity and outer membrane disruption

Microbial Biotechnolog

Національні тенденції розвитку університетської освіти

В сучасному динамічно змінюваному світі університет - це перш за все вищий навчальний заклад, який є індикатором цивілізаційності регіону та держави. Проте у наші дні класичні університети постали перед серйозними викликами часу.В современном динамически изменяющемся мире университет - это прежде всего высшее учебное заведение, которое является индикатором цивилизационности региона и государства. Однако в наши дни классические университеты встали перед серьезными вызовами времени

A β-hairpin epitope as novel structural requirement for protein arginine rhamnosylation

For canonical asparagine glycosylation, the primary amino acid sequence that directs glycosylation at specific asparagine residues is well-established. Here we reveal that a recently discovered bacterial enzyme EarP, that transfers rhamnose to a specific arginine residue in its acceptor protein EF-P, specifically recognizes a beta-hairpin loop. Notably, while the in vitro rhamnosyltransferase activity of EarP is abolished when presented with linear substrate peptide sequences derived from EF-P, the enzyme readily glycosylates the same sequence in a cyclized beta-hairpin mimic. Additional studies with other substrate-mimicking cyclic peptides revealed that EarP activity is sensitive to the method used to induce cyclization and in some cases is tolerant to amino acid sequence variation. Using detailed NMR approaches, we established that the active peptide substrates all share some degree of beta-hairpin formation, and therefore conclude that the beta-hairpin epitope is the major determinant of arginine-rhamnosylation by EarP. Our findings add a novel recognition motif to the existing knowledge on substrate specificity of protein glycosylation, and are expected to guide future identifications of rhamnosylation sites in other protein substrates

Synthetic studies with bacitracin A and preparation of analogues containing alternative zinc binding groups

Microbial Biotechnolog