Mastering the Gram-negative bacterial barrier – Chemical approaches to increase bacterial bioavailability of antibiotics

Ropponen, Henni-Karoliina; Richter, Robert; Hirsch, Anna K. H.; Lehr, Claus‐Michael

doi:10.1016/j.addr.2021.02.014

Cited by 47 publications

(50 citation statements)

References 234 publications

(299 reference statements)

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“…For compounds acting on intracellular bacterial targets (i.e. targets located in the cytoplasm), the processes of compound influx and prevention of efflux (especially so for Gram-negative bacteria as a result of their complex cell envelope and presence of numerous multidrug efflux pumps) are both critical optimization parameters to ensure sufficient target engagement 249 – 253 . These factors can be addressed by suitable compound design, which generally remains rather empirical and challenging 254 – 257 .…”

Section: Advancing Hits To (Pre)clinical Statusmentioning

confidence: 99%

Towards the sustainable discovery and development of new antibiotics

et al. 2021

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An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.

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Section: Advancing Hits To (Pre)clinical Statusmentioning

confidence: 99%

Towards the sustainable discovery and development of new antibiotics

et al. 2021

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“…In synergy with shape changes, bacteria can actively regulate antibiotic concentration inside of the cell by controlling porin and efflux-pump expressions (Fig. 1B) [45,46]. Cell-wall targeting antibiotics, such as β -lactams that disrupt the stability of the peptidoglycan meshwork are translocated by OmpF porins to induce envelope-stress response (CpX) [47].…”

Section: Discussionmentioning

confidence: 99%

Antibiotic resistance via bacterial cell shape-shifting

Ojkic

Serbanescu

Banerjee

2021

Preprint

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Bacteria have evolved to develop multiple strategies for antibiotic resistance by effectively reducing intracellular antibiotic concentrations or antibiotic binding affinities, but the role of cell morphology on antibiotic resistance remains poorly characterized. By analyzing cell morphological data of different bacterial species under antibiotic stress, we find that bacterial cells robustly reduce surface-to-volume ratio in response to most types of antibiotics. Using quantitative modelling we show that by reducing surface-to-volume ratio, bacteria can effectively reduce intracellular antibiotic concentration by decreasing antibiotic influx. The model predicts that bacteria can increase surface-to-volume ratio to promote antibiotic dilution if efflux pump activity is reduced, in agreement with data on membrane-transport inhibitors. Using the particular example of ribosome-targeting antibiotics, we present a systems-level model for the regulation of cell shape under antibiotic stress, and discuss feedback mechanisms that bacteria can harness to increase their fitness in the presence of antibiotics.

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“…High permeability through microbial cell wall increase efficacy while decreased permeability may give rise to antimicrobial resistance. The ideal logP of active molecules against Gram-negative bacteria was around four, and six, respectively [ 63 ].…”

Section: Cheminformatics Techniques In Antimicrobial Drug Discovery and Developmentmentioning

confidence: 99%

Cheminformatic Characterization of Natural Antimicrobial Products for the Development of New Lead Compounds

2021

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The growing antimicrobial resistance (AMR) of pathogenic organisms to currently prescribed drugs has resulted in the failure to treat various infections caused by these superbugs. Therefore, to keep pace with the increasing drug resistance, there is a pressing need for novel antimicrobial agents, especially from non-conventional sources. Several natural products (NPs) have been shown to display promising in vitro activities against multidrug-resistant pathogens. Still, only a few of these compounds have been studied as prospective drug candidates. This may be due to the expensive and time-consuming process of conducting important studies on these compounds. The present review focuses on applying cheminformatics strategies to characterize, prioritize, and optimize NPs to develop new lead compounds against antimicrobial resistance pathogens. Moreover, case studies where these strategies have been used to identify potential drug candidates, including a few selected open-access tools commonly used for these studies, are briefly outlined.

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Mastering the Gram-negative bacterial barrier – Chemical approaches to increase bacterial bioavailability of antibiotics

Cited by 47 publications

References 234 publications

Towards the sustainable discovery and development of new antibiotics

Towards the sustainable discovery and development of new antibiotics

Antibiotic resistance via bacterial cell shape-shifting

Cheminformatic Characterization of Natural Antimicrobial Products for the Development of New Lead Compounds

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