BacPROTACs mediate targeted protein degradation in bacteria

Morreale, Francesca; Kleine, Stefan; Leodolter, Julia; Junker, Sabryna; Hoi, David M.; Ovchinnikov, Stepan; Okun, Anastasia; Kley, Juliane; Kurzbauer, R; Junk, Lukas; Guha, Somraj; Podlesainski, David; Kazmaier, Uli; Boehmelt, Guido; Weinstabl, Harald; Rumpel, Klaus; Schmiedel, Volker Martin; Hartl, Markus; Haselbach, David; Meinhart, Anton; Kaiser, Markus; Clausen, Tim

doi:10.1016/j.cell.2022.05.009

Cited by 93 publications

(109 citation statements)

References 85 publications

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“…We validated the formation of this structural state by multiple techniques and by showing that mutating a conserved aromatic residue, which is obligatory for resting state formation by Sa ClpC, also triggers constitutive hexamer formation and activation of ClpC1. A recent study also documents resting state formation for Bs ClpC ( 32 ), indicating that ClpC activity control via MD-mediated resting state formation is widespread and evolutionarily conserved.…”

Section: Discussionmentioning

confidence: 88%

Antibacterial peptide CyclomarinA creates toxicity by deregulating the Mycobacterium tuberculosis ClpC1–ClpP1P2 protease

Taylor

Frommherz

Katikaridis

et al. 2022

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 88%

Antibacterial peptide CyclomarinA creates toxicity by deregulating the Mycobacterium tuberculosis ClpC1–ClpP1P2 protease

Taylor

Frommherz

Katikaridis

et al. 2022

Journal of Biological Chemistry

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“…52 The Clp protease system could be analogously hijacked through the engineering of chimeric molecules that target proteolysis of specific proteins in bacteria. 53 One example of a target protein is FtsZ, discussed below.…”

Section: ■ Many Worthy Targets Lack Good Leads Despite Harboring Drug...mentioning

confidence: 99%

Prospects for Antibacterial Discovery and Development

et al. 2021

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The rising prevalence of multidrug-resistant bacteria is an urgent health crisis that can only be countered through renewed investment in the discovery and development of antibiotics. There is no panacea for the antibacterial resistance crisis; instead, a multifaceted approach is called for. In this Perspective we make the case that, in the face of evolving clinical needs and enabling technologies, numerous validated antibacterial targets and associated lead molecules deserve a second look. At the same time, many worthy targets lack good leads despite harboring druggable active sites. Creative and inspired techniques buoy discovery efforts; while soil screening efforts frequently lead to antibiotic rediscovery, researchers have found success searching for new antibiotic leads by studying underexplored ecological niches or by leveraging the abundance of available data from genome mining efforts. The judicious use of “polypharmacology” (i.e., the ability of a drug to alter the activities of multiple targets) can also provide new opportunities, as can the continued search for inhibitors of resistance enzymes with the capacity to breathe new life into old antibiotics. We conclude by highlighting available pharmacoeconomic models for antibacterial discovery and development while making the case for new ones.

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“…98 The utility of this degradation modality was very recently exemplified by the group of Clausen with the development of BacPROTACs. 99 BacPROTACS are described in further detail below.…”

Section: Acs Infectious Diseasesmentioning

confidence: 99%

“…Conceivably, degradation activity would be dependent on the interaction of the POI with the proteolytic chamber and/or unfoldase partner and the degrader's ability to form a stable ternary complex between the two elements. 40 The recent development of BacPROTACs by Clausen et al 99 elegantly addresses several of the aforementioned concepts. The conceptualization of BacPROTACs started from the design of a bifunctional degrader, supported by highresolution crystal structures, consisting of a pArg tag (to engage the amino terminal domain of ClpC) tethered to a chemical linker terminating with biotin (to bind the model POI streptavidin).…”

Section: Acs Infectious Diseasesmentioning

confidence: 99%

“…The authors then extended the concept by demonstrating the successful in vitro degradation of the human protein BRDT in mycobacteria. 99 To do this, they used JQ1 as the warhead to engage the bromodomain-1 (BD1) in concert with a simplified analogue of CymA, which is a mycobacterial cell permeable cyclic peptide known to interact with the N-terminal region of ClpC1. By using M. smegmatis cells stably expressing the BRDTBD1 protein, they were able to demonstrate concentration-dependent degradation of BRDTBD1 with their refined BacPROTAC.…”

Section: Acs Infectious Diseasesmentioning

confidence: 99%

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Targeted Protein Degradation: The New Frontier of Antimicrobial Discovery?

2021

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Targeted protein degradation aims to hijack endogenous protein quality control systems to achieve direct knockdown of protein targets. This exciting technology utilizes event-based pharmacology to produce therapeutic outcomes, a feature that distinguishes it from classical occupancy-based inhibitor agents. Early degrader candidates display resilience to mutations while possessing potent nanomolar activity and high target specificity. Paired with the rapid advancement of our knowledge in the factors driving targeted degradation, the expansion of this style of therapeutic agent to a range of disease indications is eagerly awaited. In particular, the area of antibiotic discovery is sorely lacking in novel approaches, with the Antimicrobial Resistance (AMR) crisis looming as the next potential global health calamity. Here, the current advances in targeted protein degradation are highlighted, and potential approaches for designing novel antimicrobial protein degraders are proposed, ranging from adaptations of current strategies to completely novel approaches to targeted protein degradation.

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BacPROTACs mediate targeted protein degradation in bacteria

Cited by 93 publications

References 85 publications

Antibacterial peptide CyclomarinA creates toxicity by deregulating the Mycobacterium tuberculosis ClpC1–ClpP1P2 protease

Antibacterial peptide CyclomarinA creates toxicity by deregulating the Mycobacterium tuberculosis ClpC1–ClpP1P2 protease

Prospects for Antibacterial Discovery and Development

Targeted Protein Degradation: The New Frontier of Antimicrobial Discovery?

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