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

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.

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.

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…

Can effective synergists be identified to enhance the effect of antibiotics against Gram negative pathogens?

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.

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…

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.

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.

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

Examining the therapeutic potential of new semisynthetic lipopeptide antibiotics

Ontwikkeling van resistentie tegen antibiotica kan optreden als patiënten onnodig of te lang met antibiotica behandeld worden. Diagnostiek waarmee snel een bacteriële infectie vastgesteld kan worden, of de response op antibiotica bepaald kan worden, zijn daarom belangrijk om therapie te optimaliseren…

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.’

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.

Gubbens

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.

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

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…

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…

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

Aim of the proposal is to develop lugdunomycin into a drug candidate able to treat infectious diseases caused by multi-drug resistant pathogens.

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…

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.

Professor Biological chemistry Nathaniel Martin from the Institute of Biology Leiden is interviewed by the Netherlands Innovation Network on innovative scientific approaches. He talks about his work on designing new antibiotics and developing new molecules to make resistant bacteria susceptible again…

This project aims to assess the risk of spread of antimicrobial resistance genes in the environment derived from currently used synthetic biology approaches in the field of drug discovery.

As a non-invasive genetic method, eDNA based approaches have become an important component of ecologists' and environmental managers' toolkits for biomonitoring in conservation and an increasingly important source of ecological knowledge.

Utilization of plant-originated products as new antibiotics

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.

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

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,…

Can the pink-pigmented microbe Methylobacterium extorquens be genetically engineered to convert the sustainable raw material methanol into antibiotics?

The bacterial cell wall is a nearly universal structure that offers protection and gives the cell its shape. However, environmental stressors, such as cell wall-targeting antibiotics and hyperosmotic conditions, can induce bacteria to shift to a wall-deficient state. It is unknown whether the lack of…

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.

Can new variants of daptomycin and the polymyxins be found?

Can we make a better vancomycin?

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.

Explaining treatment response variability between and within patients can support treatment and dosing optimization, to improve treatment of individual patients.

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).

How can cell wall engineering approaches be used to improve streptomycetes for industry to make new antibiotics?

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

Knowledge of mental distress and resilience factors over the time span from before to after a stressor is important to be able to leverage the most promising resilience factors and promote mental health at the right time. To shed light on this topic, we designed the RESIST Study, in which we assessed…

Biosynthetic gene clusters (BGCs) for natural products are widespread in microbial genomes, and they are rapidly exchanged. This research assesses the factors that control the spread of BGCs and resistance genes in nature. This includes risk assessment for the spread of engineered DNA in nature.

The Quantitative Pharmacology group headed by Coen van Hasselt focusses on the application of state-of-the-art quantitative pharmacometrics and systems pharmacology modeling combined with translational experimental models to develop personalized treatment strategies for antibiotics and to combat antimicrobial…

Can metabolomic profiling be used to predict resistance against insect herbivores in plants?

German scientists and NASA have developed a bacteria-killing coating for space toilets. With this coating they hope to protect astronauts in space stations from pathogens. Professor of Biological chemistry Nathaniel Martin sheds light on the discovery: 'You don't expect nasty bacteria up there, but…

Promotors: C.A.J. Knibbe, Anthonius de Boer, Co-promotor: M.M.J. van der Vorst

One of the stained glass windows in the Great Auditorium of the Academy Building is dedicated to the students and staff of Leiden University who resisted, protested against, or became victims of the German occupiers. It depicts female figures alongside male ones.

Natural product inspired antibiotics to address resistance

Can cyclic peptides provide a new generation of antibiotics?