Antibiotic drug development

The extensive use of antibiotics, in both clinical and agricultural settings, are one of the major factors contributing to the emergence of antibiotic resistance. Such resistance, in combination with the lack of development of novel antibiotics heightens the urgency to develop novel and effective therapies for the treatment of infectious diseases.

This thesis describes efforts to contribute to the field of antibiotic drug discovery, by focusing on repurposing niclosamide (here by named ATx201) as a potent decolonization agent targeting Staphylococcus aureus in atopic dermatitis lesions. In addition, by using S. aureus as the model organism, the novel mode of action of ATx201 towards bacteria is described, together with a reduced likelihood of developing resistance and ability to reduce S. aureus bacterial load in atopic dermatitis lesions.

Given the consistent antimicrobial properties of ATx201 towards Gram-positive bacteria, specifically S. aureus, we further investigated the antimicrobial potential and potential improvement of other pharmacological properties of newly synthesized ATx201 derivatives against a broader panel of clinically important bacteria, including multidrug resistant Gramnegative bacteria.

Here, several derivatives were identified as active and we showed that when in combination with a compound that disrupts the outer membrane, ATx201 and other derivatives are potentiated against Gram-negative bacteria, specifically Escherichia coli. Overall, our data suggests that ATx201 and derivatives could represent a potent alternative for the treatment of infections caused by multidrug resistant bacteria.

Additionally, we evaluated the resistance rates of S. aureus (recovered from environmental settings) towards antibiotics used in clinical and veterinary practice. Given the high rates of resistance observed, this study further highlights the need to develop new antibiotics. In conclusion, the work conducted in this thesis contributes to the field of antibiotic drug discovery by providing knowledge about possible new antibiotic therapies, with low potential to generate resistance in bacteria