Broad-spectrum antibiotic | EPFL Graph Search

A broad-spectrum antibiotic is an antibiotic that acts on the two major bacterial groups, Gram-positive and Gram-negative, or any antibiotic that acts against a wide range of disease-causing bacteria. These medications are used when a bacterial infection is suspected but the group of bacteria is unknown (also called empiric therapy) or when infection with multiple groups of bacteria is suspected. This is in contrast to a narrow-spectrum antibiotic, which is effective against only a specific group of bacteria. Although powerful, broad-spectrum antibiotics pose specific risks, particularly the disruption of native, normal bacteria and the development of antimicrobial resistance. An example of a commonly used broad-spectrum antibiotic is ampicillin. Bacterial targets Antibiotics are often grouped by their ability to act on different bacterial groups. Although bacteria are biologically classified using taxonomy, disease-causing bacteria have historically b

Broad-spectrum Antiviral Nanoparticles

Marie Müller

Viral infections affect millions of people every year, yet broad-spectrum virucidal therapies are not available. Antiviral substances in current use act on specific viral mechanisms against only a small number of viruses. Virustatic materials interfere with the viral infection cycle before the cells become infected. By targeting highly conserved attachment receptors, they can be broad-spectrum and non-toxic. However, their reversible virus binding renders them ineffective in-vivo and therapeutically irrelevant. Broad-spectrum virucidal substances that irreversibly inhibit viral infectivity do exist, but are too toxic for therapeutic applications. An ideal antiviral method would be broad-spectrum, virucidal instead of virustatic and therefore irreversible, and non-toxic. The scientific literature describes gold-nanoparticles (NPs) with 2-mercaptoethanesulfonate (MES) ligands as virustatic since these NPs only bind reversibly to viral attachment ligands. In our research group, we postulated that by lengthening the ligands to 11-mercapto-1-undecanesulfonate (MUS), their binding would be stronger and induce a force on the viruses sufficient to damage the virus irreversibly. Virological testing indicated that these MUS NPs do exhibit a virucidal effect against a wide range of viruses. The present study was able to show the structural damage to viruses in their near-native state imaged in cryo-electron microscopy (cryoEM). We found that while virustatic MES NPs attach only in small numbers to the viruses virucidal MUS NPs avidly attach to viruses and show a clear progression towards fully NP-covered viruses, which we interpret as the morphology of the virucidal endpoint. The analysis of the immediate interaction of virucidal NPs and viruses showed that virucidal NPs bind to proteins vital to the viral infection cycle: (1) Virucidal NPs bind to glycoproteins on the viral envelope that exert a force onto the viral envelope leading to envelope breakage. (2) Virucidal NPs attach to released viral capsids that break upon interaction with virucidal NPs and become fully NP covered, which is the morphology of the virucidal endpoint. This project provided an opportunity to advance the field of NPs â based antivirals. It is the first study to provide a solution-state visualisation of the interaction of viruses and virucidal NPs. The study further offers important insight to the association of single NPs with viral proteins of the envelope and virus capsid as well as their effect upon them, and offers a new approach for the future of broad-spectrum non-toxic virucidal therapies. Keywords Nanoparticles, Viruses, CryoEM, CryoET, broad-spectrum antivirals, virustatic, virucidal, HSPG, HSV

EPFL2017

Novel broad-spectrum virucidal antivirals

Matteo Gasbarri

The current COVID-19 pandemic has showed the threats that viruses can cause to the whole world. Over 200 million infections and over 4.5 million deaths and enormous socio-economic impact were the output of the emergence of a single new pathogen: SARS-CoV-2. The development of vac-cines is the paramount solution to overcome the pandemic. However, even with extraordinary and unprecedented worldwide efforts, it took almost one year to have a first validated vaccine and it will take longer to have a global vaccination. In addition, vaccines are preventive drugs, that need to be administered before the infection to stimulate the immune-system of the patient. In the meanwhile, in case of an infection, we were harmless in the fight against the virus.Antivirals are curative drugs, that inhibit one step of the viral replication. Many approaches have been investigated: antibodies, peptides, peptomimics, small molecules. Most of them are specif-ic to a single family of virus, making the development slow and expensive. Entry inhibitors are a class of antivirals that binds to the virus, preventing the attachment to the cell membrane. Such antivirals usually have a broad-spectrum of action, since they mimic cell receptors, such as heparan sulfate pro-teoglycans (HSPGs), exploited by different viruses. Many compounds have been developed throughout the years; however, the reversible nature of the virus inhibition mechanism has prevented their trans-lation to the clinic. Our group has recently shown that the simple addition of a long hydrophobic linker makes the inhibition irreversible, proving this hypothesis with two compounds: gold-nanoparticles and beta-cyclodextrins. The goal of this thesis is to develop novel antivirals able to inhibit a broad-spectrum of viruses with an irreversible mechanism of action and to investigate the key features responsible of such properties. In this thesis, we further expand the broad-spectrum activity of gold-nanoparticles and beta-cyclodextrins showing that they are capable of inhibiting viruses beyond HSPG-dependent ones. In addition, we show their ability of reversibly inactivating SARS-CoV-2. Moreover, we have investigated the role of the hydrophobic linker's length in the virucidal inhibition in case of cyclodextrins, proving the need of such moiety to have an irreversible viral inactivation. Envisioning a translation of such drug, we have performed a preliminar pharmacokinetic study performed via intranasal administration.A novel class of compounds has been also proposed: sulfated/sulfonated dendritic polyglyc-erol. A broad investigation of the molecular design rules needed to achieve nanomolar irreversible viral inhibition is discussed. We also show that the most active compound proves to be active against HSV-2 and RSV, thus with a broad-spectrum activity. In addition, we demonstrate that the virucidal activity is leading to the release of viral DNA upon interaction between the virus and our dendritic polyglycerol. A different modification of dendritic polyglycerol, bearing carboxylic acid, showed activi-ty against SARS-CoV-2; such inhibition results to be irreversible. This compound has been further test-ed in a hamster model, where initial studies confirm its feasibility as antiviral. In addition to these studies on development of virucidal antivirals, different technological so-lutions to prevent viral spreading are proposed. In particular, we focused on an antiviral filter and antiviral surfaces.

EPFL2021

Innovative Tools and in vivo Methods for Tuberculosis Drug Discovery and Development

Raphael Christopher Sommer

Worldwide, tuberculosis (TB) is the leading cause of death due to a single infectious agent, claiming 1.6 million human lives and causing >10 million new cases in 2017 alone, mostly in low-income regions. The intracellular pathogen Mycobacterium tuberculosis is the etiological agent and generally infects the lungs. Although treatments exist, curing TB requires long and often expensive chemotherapy, frequently accompanied by undesirable side-effects. In the absence of an effective vaccine and with the increasing emergence of multidrug resistance, new and more powerful antibiotics are urgently needed to control the global TB crisis. In this respect, benzothiazinones (BTZs), a class of new anti-TB compounds, have recently been discovered. Macozinone (PBTZ169), that has reached phase I and II clinical trials in Switzerland and Russia, respectively, is undoubtedly the most promising drug of this category. We derivatized PBTZ169 into a fluorescent chemical probe that efficiently, covalently and selectively labels the enzyme DprE1, thereby localizing the target of BTZs to the periplasm at the poles of actinobacteria. We further discuss the potential applications of such probes for in vivo imaging, mycobacterial detection and designing new diagnostic tools. In general, the search for novel anti-mycobacterial drugs is an extremely long process, delaying the progression of new compounds down the pipeline and to the clinic. Assessing drug efficacy in vivo typically requires extensive resources and is time-consuming. This process can be shortened by applying alternative and innovative methods devised in this thesis, namely the implementation of in vivo imaging procedures and use of the zebrafish embryo model of mycobacterial infection for drug discovery and development. In vivo imaging enables bacterial loads in animal models to be assessed in real time, by means of fluorescence or bioluminescence imaging. We constructed, optimized and characterized genetically engineered near-infrared fluorescent reporters of the pathogens Mycobacterium marinum and M. tuberculosis that allow direct visualization of bacteria in infected zebrafish and mice, respectively. Furthermore, we show that the fluorescence level accurately reflects the bacterial load, as determined by colony forming unit enumeration, thus enabling the efficacy of antibiotic treatment to be assessed in live animals. Alternatively, we applied autobioluminescent M. tuberculosis to evaluate drug efficacy in mice and demonstrated that our system enables the therapeutic response to be followed in real time. Longitudinal imaging also reduces the number animals required thus providing a substantial gain of time and resources. Finally, the zebrafish embryo is an inexpensive and faster alternative model that has been applied to investigate mycobacterial pathogenesis. We implemented this model of M. marinum infection and successfully applied it to assess the activity of several drugs in vivo. Altogether, the innovative methods described in this work are advantageous for TB drug discovery and development, especially for the in vivo evaluation of new anti-mycobacterial candidates, and provide more ethically acceptable approaches and biomedical applications.

EPFL2019