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.

The impact of the phenotypic plasticity of P. aeruginosa and the distinct CF lung microenvironments on antibiotic drug effects and resistance remains poorly understood.

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

Antibioticaresistentie is een van de grootste bedreigingen wereldwijd voor de volksgezondheid in de komende decennia.

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.

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.

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

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…

This thesis tackles the urgent challenge of antimicrobial resistance (AMR) through the design of novel antibacterial agents.

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.

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.

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.

This thesis examines strategies to address the global threat of antimicrobial resistance (AMR). Antimicrobial resistance poses an increasing global health risk, highlighting the need for new treatments against Gram-negative pathogens.

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.

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.

Obesity may alter how a person absorbs, distributes, metabolizes or excretes medication. This thesis describes how obesity affects drug levels in the blood for antimicrobial agents, such as ciprofloxacin and fluconazole.

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…

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.

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

The increasing resistance of pathogenic bacteria to antibiotics necessitates the discovery of new medicines.

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.

Hoe kunnen we efficiënte chemische synthese en klinische microbiologie combineren om nieuwe antibiotica tegen Clostridioides difficile-infecties te ontwikkelen?

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…

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.

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

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…

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.

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

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

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

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.