Unrealized targets in the discovery of antibiotics for Gram-negative bacterial infections

Theuretzbacher, Ursula; Blasco, Benjamin; Duffey, Maëlle; Piddock, Laura J. V.

doi:10.1038/s41573-023-00791-6

Cited by 27 publications

(9 citation statements)

References 291 publications

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“…Three of the four complexes, Bam, Lpt and Lol, are also essential across other pathogenic gram-negative bacterial species and have been the focus of intense antibiotic discovery efforts over the past decade. 7 mini-PROSPECT is the first attempt to identify target-specific inhibitors for these important essential OMP/OMAPs in P. aeruginosa by combining a whole cell phenotypic screen with a knockdown-based genetic strategy.…”

Section: Discussionmentioning

confidence: 99%

“Multiplexed screen identifies aPseudomonas aeruginosa-specific small molecule targeting the outer membrane protein OprH and its interaction with LPS”

Poulsen,

Warrier,

Barkho

et al. 2024

Preprint

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The surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against Pseudomonas aeruginosa, a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of P. aeruginosa combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging. We adapted PROSPECT1, a target-based, whole-cell screening strategy, to discover small molecule probes that kill P. aeruginosa mutants depleted for essential proteins localized at the OM. We identified BRD1401, a small molecule that has specific activity against a P. aeruginosa mutant depleted for the essential lipoprotein, OprL. Genetic and chemical biological studies identified that BRD1401 acts by targeting the OM β-barrel protein OprH to disrupt its interaction with LPS and increase membrane fluidity. Studies with BRD1401 also revealed an interaction between OprL and OprH, directly linking the OM with peptidoglycan. Thus, a whole-cell, multiplexed screen can identify species-specific chemical probes to reveal novel pathogen biology.

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Section: Discussionmentioning

confidence: 99%

“Multiplexed screen identifies aPseudomonas aeruginosa-specific small molecule targeting the outer membrane protein OprH and its interaction with LPS”

Poulsen,

Warrier,

Barkho

et al. 2024

Preprint

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“…Application of this information could have multiple uses in actively modulating cellular function. Some will serve as excellent drug targets, but the tendency for bacteria to build redundancy into their small molecule transporters means that in many cases they will not be suitable targets [159]; however, their manipulation during biotechnological processes to limit the flow of a nutrient and/or product in or out of the cell is certainly possible, although to date examples of 'transporter engineering' sit around changing transporter profiles through manipulating gene expression rather than protein activity [160][161][162]. We hope this review serves as a useful summary of what is known and act as a catalyst for more study in this area.…”

Section: Discussionmentioning

confidence: 99%

Flipping the switch: dynamic modulation of membrane transporter activity in bacteria

Elston,

Mulligan,

Thomas

2023

Microbiology

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The controlled entry and expulsion of small molecules across the bacterial cytoplasmic membrane is essential for efficient cell growth and cellular homeostasis. While much is known about the transcriptional regulation of genes encoding transporters, less is understood about how transporter activity is modulated once the protein is functional in the membrane, a potentially more rapid and dynamic level of control. In this review, we bring together literature from the bacterial transport community exemplifying the extensive and diverse mechanisms that have evolved to rapidly modulate transporter function, predominantly by switching activity off. This includes small molecule feedback, inhibition by interaction with small peptides, regulation through binding larger signal transduction proteins and, finally, the emerging area of controlled proteolysis. Many of these examples have been discovered in the context of metal transport, which has to finely balance active accumulation of elements that are essential for growth but can also quickly become toxic if intracellular homeostasis is not tightly controlled. Consistent with this, these transporters appear to be regulated at multiple levels. Finally, we find common regulatory themes, most often through the fusion of additional regulatory domains to transporters, which suggest the potential for even more widespread regulation of transporter activity in biology.

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“…It has been observed that TolC is only required in minimal amounts to assemble with the AcrAB complex, 207 and therefore, total depletion of TolC would be required by any potential TolC inhibitor, which may prove very difficult because of the "target vulnerability," as recently described in our publication on target-centric drug discovery. 208 New studies focusing on bacteriocin transport into Gramnegative bacteria, such as klebicin (KlebC) from K. pneumoniae 209 and colicin E1 (ColE1) from E. coli, 210 indicate that both toxins bind to TolC to allow transportation into the cell, and this interaction results in blocked drug efflux. KlebC associates with TonB and likely uses the efflux channel as both its OM receptor and translocator.…”

Section: Acs Infectious Diseasesmentioning

confidence: 99%

“…However, as there is little published literature in this area, this may suggest it is difficult to inhibit TolC activity. It has been observed that TolC is only required in minimal amounts to assemble with the AcrAB complex, and therefore, total depletion of TolC would be required by any potential TolC inhibitor, which may prove very difficult because of the “target vulnerability,” as recently described in our publication on target-centric drug discovery …”

Section: Anti-efflux Strategiesmentioning

confidence: 99%

Extending the Potency and Lifespan of Antibiotics: Inhibitors of Gram-Negative Bacterial Efflux Pumps

Duffey,

Jumde,

da Costa

et al. 2024

ACS Infect. Dis.

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Efflux is a natural process found in all prokaryotic and eukaryotic cells that removes a diverse range of substrates from inside to outside. Many antibiotics are substrates of bacterial efflux pumps, and modifications to the structure or overexpression of efflux pumps are an important resistance mechanism utilized by many multidrug-resistant bacteria. Therefore, chemical inhibition of bacterial efflux to revitalize existing antibiotics has been considered a promising approach for antimicrobial chemotherapy over two decades, and various strategies have been employed. In this review, we provide an overview of bacterial multidrug resistance (MDR) efflux pumps, of which the resistance nodulation division (RND) efflux pumps are considered the most clinically relevant in Gram-negative bacteria, and describe over 50 efflux inhibitors that target such systems. Although numerous efflux inhibitors have been identified to date, none have progressed into clinical use because of formulation, toxicity, and pharmacokinetic issues or a narrow spectrum of inhibition. For these reasons, the development of efflux inhibitors has been considered a difficult and complex area of research, and few active preclinical studies on efflux inhibitors are in progress. However, recently developed tools, including but not limited to computational tools including molecular docking models, offer hope that further research on efflux inhibitors can be a platform for research and development of new bacterial efflux inhibitors.

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Unrealized targets in the discovery of antibiotics for Gram-negative bacterial infections

Cited by 27 publications

References 291 publications

“Multiplexed screen identifies aPseudomonas aeruginosa-specific small molecule targeting the outer membrane protein OprH and its interaction with LPS”

“Multiplexed screen identifies aPseudomonas aeruginosa-specific small molecule targeting the outer membrane protein OprH and its interaction with LPS”

Flipping the switch: dynamic modulation of membrane transporter activity in bacteria

Extending the Potency and Lifespan of Antibiotics: Inhibitors of Gram-Negative Bacterial Efflux Pumps

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