Antibacterial New Target Discovery: Sentinel Examples, Strategies, and Surveying Success

Sutterlin, Holly A.; Malinverni, Juliana C.; Lee, Sang Ho; Balibar, Carl J.; Roemer, Terry

doi:10.1007/7355_2016_31

Cited by 12 publications

(9 citation statements)

References 129 publications

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“…Deciphering the RcsF/OMP assembly pathway not only would be highly informative for a further mechanistic understanding of this versatile macromolecular machinery but might also open the doors for novel therapeutic development strategies. The Bam complex has emerged as a major antibiotic target due to its central and essential role in the biogenesis of the OM, the primary factor of intrinsic antibiotic resistance in Gram-negative bacteria (36–38). Previous studies have explored the possibility of using OMP-derived-peptides that mimic native OMP substrates to inhibit the Bam complex via BamD (5).…”

Section: Discussionmentioning

confidence: 99%

Improper Coordination of BamA and BamD Results in Bam Complex Jamming by a Lipoprotein Substrate

Tata

Konovalova

2019

mBio

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The β-barrel assembly machinery, the Bam complex, is central to the biogenesis of integral outer membrane proteins (OMPs) as well as OMP-dependent surface-exposed lipoproteins, such as regulator of capsule synthesis protein F (RcsF). Previous genetic analysis established the model that nonessential components BamE and BamB have overlapping, redundant functions to enhance the kinetics of the highly conserved BamA/BamD core. Here we report that BamE plays a specialized nonredundant role in the Bam complex required for surface exposure of RcsF. We show that the lack of bamE, but not bamB, completely abolishes assembly of RcsF/OMP complexes and establish that the inability to assemble RcsF/OMP complexes is a molecular reason underlying all synthetic lethal interactions of ΔbamE. Our genetic analysis and biochemical cross-linking suggest that RcsF accumulates on BamA when BamA cannot engage with BamD because of its limited availability or the incompatible conformation. The role of BamE is to promote proper coordination of RcsF-bound BamA with BamD to complete OMP assembly around RcsF. We show that in the absence of BamE, RcsF is stalled on BamA, thus blocking its function, and we identify the lipoprotein RcsF as a bona fide jamming substrate of the Bam complex. IMPORTANCE The β-barrel assembly machinery, the Bam complex, consists of five components, BamA to -E, among which BamA and BamD are highly conserved and essential. The nonessential components are believed to play redundant roles simply by improving the rate of β-barrel folding. Here we show that BamE contributes a specific and nonoverlapping function to the Bam complex. BamE coordinates BamA and BamD to form a complex between the lipoprotein RcsF and its partner outer membrane β-barrel protein, allowing RcsF to reach the cell surface. In the absence of BamE, RcsF accumulates on BamA, thus blocking the activity of the Bam complex. As the Bam complex is a major antibiotic target in Gram-negative bacteria, the discovery that a lipoprotein can act as a jamming substrate may open the door for development of novel Bam complex inhibitors.

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Section: Discussionmentioning

confidence: 99%

Improper Coordination of BamA and BamD Results in Bam Complex Jamming by a Lipoprotein Substrate

Tata

Konovalova

2019

mBio

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“…Previous reviews have already presented overviews of both traditional (e.g.m etabolic labeling of biological macromolecules with radioactive precursors) and current methods for identification of the target of new antibiotic compounds. [110][111][112] Many approaches for the identification of antibacterial targets are based on the generation of resistant mutants, which are subsequently sequenced to identify altered cellular targets.T he advancement of sequencing technologies nowadays allows the cost-efficient analysis of DNAa nd RNA samples and has established chemical genomic methods as aw idely applied method for the study of the MoA of new antimicrobial compounds.T he generation of barcoded deletion mutant libraries in which each mutant is encoded by aspecific DNA-sequence allows parallel resistance screening of all mutants directly in one vessel. This technology was first reported for yeast and since been applied also in E. coli.…”

Section: Target Identification and Validationmentioning

confidence: 99%

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

et al. 2018

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The public view on antibiotics as reliable medicines changed when reports about "resistant superbugs" appeared in the news. While reasons for this resistance development are easily spotted, solutions for re-establishing effective antibiotics are still in their infancy. This Review encompasses several aspects of the antibiotic development pipeline from very early strategies to mature drugs. An interdisciplinary overview is given of methods suitable for mining novel antibiotics and strategies discussed to unravel their modes of action. Select examples of antibiotics recently identified by using these platforms not only illustrate the efficiency of these measures, but also highlight promising clinical candidates with therapeutic potential. Furthermore, the concept of molecules that disarm pathogens by addressing gatekeepers of virulence will be covered. The Review concludes with an evaluation of antibacterials currently in clinical development. Overall, this Review aims to connect select innovative antimicrobial approaches to stimulate interdisciplinary partnerships between chemists from academia and industry.

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“…Effective antibacterial design is closely coupled to understanding of target biology, therefore research in clear connection between Mur enzyme inhibition, peptidoglycan synthesis, and whole‐cell activity should be pursued (Sutterlin, Malinverni, Lee, Balibar, & Roemer, ). On the other hand, careful inspection of bacterial efflux mechanisms coupled to thorough in vitro whole‐bacterial cell assays on multiple (wild type and efflux pump knockout) strains should provide critical data.…”

Section: Discussionmentioning

confidence: 99%

Reaching toward underexplored targets in antibacterial drug design

Jukič

Gobec

Sova

2018

Drug Development Research

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The increase of antimicrobial resistance necessitates the renewal and strong research involvement in antibacterial drug design. In the following work, we comment on the key approaches used in development of new antibacterials, focusing on intracellular therapeutic targets that have been so far mostly underexplored: the enzymes of the Mur pathway MurA to MurF. We identify common obstacles observed during research on MurA, MurB, and Mur ligases inhibitors and their development into potential antibacterial compounds, and discern several approaches and solutions to tackle the whole‐cell activity of designed compounds. Furthermore, we consolidate recent literature reports and encourage the further research on Mur enzymes.

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Antibacterial New Target Discovery: Sentinel Examples, Strategies, and Surveying Success

Cited by 12 publications

References 129 publications

Improper Coordination of BamA and BamD Results in Bam Complex Jamming by a Lipoprotein Substrate

Improper Coordination of BamA and BamD Results in Bam Complex Jamming by a Lipoprotein Substrate

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

Reaching toward underexplored targets in antibacterial drug design

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