This thesis describes the evaluation of novel natural products with antibacterial activity enabled by total chemical synthesis.

Pathogenic bacteria are increasingly resistant to today’s antibiotics. Professor Gilles van Wezel seeks new forms of antibiotics in good bacteria that live in the soil.

Vancomycin is a last-resort antibiotic for the treatment of many Gram-positive bacterial infections, while remaining inactive against Gram-negative strains.

Given the accelerating appearance of antimicrobial resistance, there is an urgent need for more fundamental research into novel antibiotic strategies. The work in this thesis helps to address this global problem by developing new antibiotic compounds, inspired by the antibacterial mechanisms of the…

With the rise of multi-drug resistant bacterial pathogens, the possibility of a post-antibiotic world is quickly becoming reality.

The investigations described in this thesis lay out strategies aimed at advancing antibiotic research and development. The examples presented revolve around two main approaches: understanding drug-target interactions and target identification.

People who have taken antibiotics in the past three months pay more attention to negative facial expressions, according to research by postdoc Katerina Johnson and assistant professor Laura Steenbergen. This may explain how antibiotics increase the risk of developing depression.

Antibiotics are a class of medicine most people take for granted. But pathogenic bacteria are becoming more and more resistant to our antibiotics, and this poses a great challenge for future treatments. There is thus a great societal need to identify new molecules that can address new targets and be…

Polymyxins are clinically used antibiotics, discovered in mid-20th century. Once abandoned due to excessive nephrotoxicity, they are now used increasingly to address infections caused by multi-drug resistant Gram-negative bacteria.In this thesis, we describe the development and synthesis of analogues…

Promotor: Prof.dr. G.P. van Wezel

Lecture

Antimicrobial resistance (AMR) is the phenomenon that pathogens become insensitive to the antibiotics that we use against them. A growing number of pathogens is becoming resistant, with methicillin-resistant S. aureus (MRSA) as the most famous example. But while the threat of AMR represents a slow-moving…

Bacteria are highly complex and diverse organisms that have adapted to survive in ecological niches ranging from the most extreme to the most heterogeneous environments.

Lecture

This thesis describes the structural and biochemical characterization of the β-lactamase BlaC from Mycobacterium tuberculosis (Mtb), and the Alr and YlmE proteins from Streptomyces coelicolor A3(2).Mtb is the main cause of tuberculosis.

Global healthcare is on the verge of an antibiotic availability crisis as bacteria have evolved resistance to nearly all known antibacterials. Identifying new antibiotics that operate via novel modes-of-action is therefore of high priority.

The prevalence of obesity (BMI >40 kg/m2) has increased rapidly over the recent years, not only in adults, but also in children and adolescents.

Enzymes are innately sensitive to changes in the amino acid sequence, which largely constrains their evolutionary potential, i.e., evolvability. This evolutionary burden can be alleviated in the presence of stabilizing mutations, which increase the buffering capacity of enzymes to tolerate mutations…

Promotor: G.P. van Wezel, Co-promotor: Y.H. Choi

Streptomyces are filamentous bacteria that produce more than two-thirds of known antibiotics.

Through his project we will unravel the global regulatory networks that control gene expression in Streptomyces bacteria and allow them to properly respond to major changes in the environment; we will then harness this knowledge to activate and identify novel antibiotics

Actinobacteria are Gram-positive bacteria that have a complex multicellular life cycle and are well known for their ability to produce a wide range of bioactive natural products (NPs).

Extending our current arsenal of antibiotics is key to staying ahead in the arms race between humans and resistant bacteria.

Timely, adequate and optimal treatment of infectious diseases is essential for the survival of patients with bacterial infections (Surviving Sepsis campaign).

Antibiotic-resistant bacteria pose a major health threat. Addressing this challenge requires among others the development of new antibacterial compounds. The research described in this thesis focuses on discovering novel antibiotics from soil bacteria, specifically Streptomyces and Paenibacillus.Despite…

Streptomyces are multicellular, Gram-positive bacteria in the phylum of actinobacteria which produce a high amount of bioactive natural products of which the expression is tightly coordinated with the life cycle.

Streptomycetes are similar to moulds, but these bacteria live in the soil. They are very popular in biotechnology because they produce a great many antibiotics and enzymes. Gilles van Wezel will be using his Vici subsidy to study ways of increasing their production.

Increasing resistance and a lack of new antibiotics are a serious problem for public health. Against this background, Gilles van Wezel of the Institute of Biology Leiden is looking for new medicines. Together with former PhD student Changsheng Wu and colleagues he discovered the special antibiotic lugdunomycin,…

Current means of fighting bacteria are no longer as good as they used to be because of antibiotic resistance. These days, people are dying from bacterial infections that could have been cured fifty years ago.

No, this isn’t about a Star Wars Alliance that wants to suppress The Resistance. Rather, the EPIC Alliance brings together scientific experts from seven countries to address the growing threat of antibiotic resistance. Leiden professor Nathaniel Martin is part of the 11-member consortium.

Bacteriophages, viruses that infect bacteria, may be used as an alternative treatment option when antibiotics fail. Leiden researchers have studied the structure and function of a novel bacteriophage that could be used to treat one of the WHO bacterial strains of concern where new treatments are urgently…

Soil bacteria can produce a wealth of antibiotics that are new to us, claims Gilles van Wezel, Professor of Molecular Biotechnology at the Institute of Biology Leiden. His research group has developed a method that can rapidly identify and produce these unknown compounds.

Biological chemist Nathaniel Martin is going to test an alternative antibiotic that can combat common resistant bacteria such as MRSA. For this purpose, he will receive 350,000 euros from the NWO's NACTAR programme. ‘We want to know how safe and effective our antibiotic is in a realistic situation.’

An international consortium of research groups is aiming to develop novel antibiotics against the tuberculosis bacteria and two other deadly bacteria. The European Union has awarded a total of 18 million euros to the RespiriTB and RespiriNTM projects. Researchers from the Leiden University Medical Centre…

Prof. Gilles van Wezel and Prof. Mike Richardson of the Institute of Biology Leiden received €1.4 million to find new antibiotics.

Antibiotic resistance, caused by widespread use of antibiotics, leads to bacterial infections that are difficult, if not impossible, to treat and is a major worldwide health concern.

Streptomyces are prolific producers of enzymes and secondary metabolites, including more than 50% of all clinical antibiotics. This makes them highly attractive for medical, biotechnological, and industrial purposes.

The soil-dwelling, filamentous bacteria of the genus Streptomyces are renowned for their production of useful secondary metabolites including antibiotics. The work described in this thesis provides new insights on the role and regulation of antibiotic production and resistance in these bacteria.

We aim to engineer streptomycetes to fully exploit their potential for natural product productions, by a rational design and evolution approach.

Bacteria use antibiotics as a weapon and even produce more antibiotics if there are competing strains nearby. This is a fundamental insight that can help find new antibiotics. Leiden scientists Daniel Rozen and Gilles van Wezel published their research results in the authoritative Proceedings of the…

Edith Schippers, Minister of Health, will be investing six million euros over the coming four years to boost research on new antibiotics. The programme will be set up by several different parties, including the Leiden Centre for Antimicrobial Research.

Antibiotic-resistant bacteria are a major problem worldwide. Molecular biologist Changsheng Wu explored innovative methods of developing new antibiotics more simply and more easily. He also discovered a new type of antibiotic.

Almost fifty scientists and twenty companies will be working on developing new antibiotics and alternatives for antibiotics use. NWO and the Ministry of Health, Wellbeing and Sport will together invest close to seven million euros in this research. Scientists from Leiden University and LUMC will be…

Antibiotic resistance is one of the major threats to human health. This week the National Antibiotic Development Platform, NADP, was officially launched via a meeting in Utrecht, with many of the stakeholders in the field present.

Filamentous Actinobacteria, such as Streptomyces, produce a plethora of chemically diverse bioactive metabolites that have found applications across medicine, agriculture and biotechnology.

A team of researchers at the Institute of Biology Leiden, in collaboration with scientists from Utrecht University, has discovered a novel approach to improve the production of antibiotics and enzymes in the soil bacteria Streptomycetes.

Sepsis is a life-threatening condition caused by a dysregulated host response to infection, it is associated with significant morbidity, mortality, and with a high financial burden on global healthcare systems. Bacterial infections are the primary cause of sepsis, but the growing prevalence of antimicrobial…

The ongoing increase in antimicrobial resistance combined with the low discovery of novel antibiotics is a serious threat to our health care.