Assessment of the rules related to gaining activity against Gram-negative bacteria

Ropponen, Henni-Karoliina; Diamanti, Eleonora; Siemens, Alexandra; Illarionov, Boris; Haupenthal, Jörg; Fischer, Markus; Rottmann, Matthias; Witschel, Matthias; Hirsch, Anna K. H.

doi:10.1039/d0md00409j

Cited by 10 publications

(16 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although this example is highly promising, some word of caution regarding the generalisability of eNTRy rules is necessary. It is currently impossible to estimate the applicability to other chemical programs as negative results typically do not get published; at least one recent publication describes the failure of this approach (Ropponen et al , 2021 ).…”

Section: The Need For New Antibioticsmentioning

confidence: 99%

Fighting antibiotic resistance—strategies and (pre)clinical developments to find new antibacterials

et al. 2022

Self Cite

View full text Add to dashboard Cite

Antibacterial resistance is one of the greatest threats to human health. The development of new therapeutics against bacterial pathogens has slowed drastically since the approvals of the first antibiotics in the early and mid-20 th century. Most of the currently investigated drug leads are modifications of approved antibacterials, many of which are derived from natural products. In this review, we highlight the challenges, advancements and current standing of the clinical and preclinical antibacterial research pipeline. Additionally, we present novel strategies for rejuvenating the discovery process and advocate for renewed and enthusiastic investment in the antibacterial discovery pipeline.

show abstract

Section: The Need For New Antibioticsmentioning

confidence: 99%

Fighting antibiotic resistance—strategies and (pre)clinical developments to find new antibacterials

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the recent 25 years, research focus shifted to the involvement of DP in the cell surface behavior in response to different environmental stimuli including charge, ionic strength, and pH [53][54][55][56][57][58][59][60]. In addition, the role of DP on compound accumulation in bacterial cells attracted research interest, in a bid to solve the fast-evolving problem of antibiotic resistance in bacteria [61][62][63][64].…”

Section: Membrane Potential (Mp) Regulates Antibiotic Transport Across the Om Of Gram-negative Bacteriamentioning

confidence: 99%

Donnan Potential across the Outer Membrane of Gram-Negative Bacteria and Its Effect on the Permeability of Antibiotics

et al. 2021

View full text Add to dashboard Cite

The cell envelope structure of Gram-negative bacteria is unique, composed of two lipid bilayer membranes and an aqueous periplasmic space sandwiched in between. The outer membrane constitutes an extra barrier to limit the exchange of molecules between the cells and the exterior environment. Donnan potential is a membrane potential across the outer membrane, resulted from the selective permeability of the membrane, which plays a pivotal role in the permeability of many antibiotics. In this review, we discussed factors that affect the intensity of the Donnan potential, including the osmotic strength and pH of the external media, the osmoregulated periplasmic glucans trapped in the periplasmic space, and the displacement of cell surface charges. The focus of our discussion is the impact of Donnan potential on the cellular permeability of selected antibiotics including fluoroquinolones, tetracyclines, β-lactams, and trimethoprim.

show abstract

“…The bottleneck in discovering new antibiotics arises from the very first steps of research due to the difficulty to find novel compounds and targets that do not exhibit cross‐resistance, as defined by the innovative criteria set by the World Health Organisation [1] . Over the past years, several rules have been developed to speed up the discovery of ideal antibiotic candidates, particularly against Gram‐negative pathogens [2] . In a review, A. L. Parkes raised the most fundamental question in antibiotic research, “what can we design for ?” [3] .…”

Section: Introductionmentioning

confidence: 99%

Exploring the Translational Gap of a Novel Class of Escherichia coli IspE Inhibitors

Ropponen,

Diamanti,

Johannsen

et al. 2023

ChemMedChem

Self Cite

View full text Add to dashboard Cite

Discovery of novel antibiotics needs multidiscliplinary approaches to gain target enzyme and bacterial activity while aiming for selectivity over mammalian cells. Here we report a multi‐parameter optimisation of a fragment‐like hit that was identified through a structure‐based virtual screening campaign on Escherichia coli IspE crystal structure. Subsequent medicinal chemistry design resulted in a novel class of E. coli IspE inhibitors, exhibiting activity also against the more pathogenic bacteria Pseudomonas aeruginosa and Acinetobacter baumannii. While cytotoxicity remains a challenge for the series, it provides new insights on the molecular properties for balancing enzymatic target and bacterial activities simultaneously as well provides new starting points for the development of IspE inhibitors with a predicted new mode of action.

show abstract

Assessment of the rules related to gaining activity against Gram-negative bacteria

Abstract: Evaluation of the applicability of Gram-negative activity rules using 16 amino acid modified compounds against a panel of Escherichia coli and its mutant strains.

Cited by 10 publications

References 42 publications

Fighting antibiotic resistance—strategies and (pre)clinical developments to find new antibacterials

Fighting antibiotic resistance—strategies and (pre)clinical developments to find new antibacterials

Donnan Potential across the Outer Membrane of Gram-Negative Bacteria and Its Effect on the Permeability of Antibiotics

Exploring the Translational Gap of a Novel Class of Escherichia coli IspE Inhibitors

Contact Info

Product

Resources

About