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

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.

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

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.

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.

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.

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

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

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.

Hoe kan de techniek van cell wall engineering worden ingezet zodat de industrie streptomyceten beter kunnen verwerken tot nieuwe antibiotica?

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.

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.

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

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

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…

Plants are colonized by an astounding number of microorganisms that can provide different life-support functions, including nutrient acquisition and protection against (a)biotic stresses like drought or pathogen attack.

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…

β-Lactamases are enzymes that can break down β-lactam substrates, such as antibiotics, preventing the use of these antibiotics for the treatment of various infectious diseases. However, some compounds, β-lactamase inhibitors, can block these enzymes allowing for possible treatments using a combination…

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.

Promotor: G.P. van Wezel

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

Streptomyces are bacteria abundant in soil that participate in diverse and complex interactions. These bacteria are the main producers of the antibiotics we currently use in the clinic.

New drugs for use as tuberculosis (TB) treatment are needed due to the constrains of classical antibiotics against TB and the rise of antibiotic-resistant strains, making TB a harder and harder disease to treat.

Promotores: Prof.dr. C.A.J. Knibbe, Prof.dr. M. Danhof, Prof.dr. K. Allegaert (Leuven)

Streptomyces bacteria are a valuable source of natural products, many of which are used in the clinic or in biotechnology.

Tuberculosis (TB) is associated with 1.5 million deaths annually. There is a need exists to optimize both current as well as novel antibiotic combination treatment strategies to improve the effectiveness and safety of treatments against TB.

This dissertation contains four works during my PhD. Different biomaterials have been designed based on coiled-coil peptides. These biomaterials have a range of applications, inclusing drug delivery, cell sorting to cell-cell fusion.

Wanneer een bacterie resistenter wordt voor het ene antibioticum, wordt het soms gevoeliger voor een ander. Om deze wisselwerking beter te begrijpen, brachten onderzoekers van het Instituut Biologie Leiden (IBL) en het Leiden Academic Centre for Drug Research (LACDR) onder leiding van Daniel Rozen en…

Streptomyces present a valuable platform for natural product discovery. Lugdunomycin is a novel angucycline-derived polyketide from Streptomyces sp QL37, with unprecedented skeleton and antimicrobial activity.

In this thesis, bioorthogonal chemistry is combined with correlative light-electron microscopy to selectively label and study pathogenic intracellular bacteria within the host immune cell.

Almost all bacteria are enveloped by a cell wall that provides cellular protection.

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

Promotor: G.A. van der Marel, Co-promotor: D.C. Codée

Promotor: G.P. van Wezel, Co-promotor: D. Claessen

Promotor: G.P. van Wezel, Co-Promotor: E. Vijgenboom

Control of infectious diseases poses continuous challenges for human health.

Mensen die de afgelopen drie maanden antibiotica hebben gebruikt, letten meer op negatieve gezichtsuitdrukkingen, blijkt uit onderzoek van postdoc Katerina Johnson en universitair docent Laura Steenbergen. Dit kan mogelijk verklaren hoe antibiotica het risico op het ontwikkelen van depressie vergroo…

The filamentous bacteria Streptomyces are widespread inhabitants of terrestrial soils.

A complex community of microbes develops in the infant gut shortly after birth. We call this community the infant gut microbiota. The microbiota influences the health of the infant, which makes the composition and function of the infant gut microbiota an important topic to study.

The effective treatment of tuberculosis (TB) remains a major challenge to global health.

Actinobacteria are well known for the production of bioactive natural products, many of which have applications in the fields of human, animal and plant health. Subject of this thesis are the anthracyclines, glycosylated aromatic polyketides with potent anticancer activity.

Promotor: C.A.J. Knibbe, Co-promotores: H.P.A. van Dongen, B. van Ramshorst