Cyclic lipopeptide antibiotics bind to the N-terminal domain of the prokaryotic Hsp90 to inhibit the chaperone activity

Minagawa, Shun; Kondoh, Yasumitsu; Sueoka, Keigo; Osada, Hiroyuki; Nakamoto, Hitoshi

doi:10.1042/bj20100743

Cited by 22 publications

(13 citation statements)

References 41 publications

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“…Thus, PMB is not only important through its direct role in inhibiting Hsp70 but may have adverse effects on its downstream network partners. Interestingly, a previous independent study proposed that PMB interacts and inhibits another chaperone, Hsp90 (Minagawa et al 2012). Hsp70 and Hs90 cooperate to facilitate fold of a special group of proteins such as kinases and steroid hormone receptors (Jackson 2013).…”

Section: Discussionmentioning

confidence: 99%

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Polymyxin B inhibits the chaperone activity of Plasmodium falciparum Hsp70

Zininga

Pooe

Makhado

et al. 2017

Cell Stress and Chaperones

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Heat shock protein 70 (Hsp70) is a molecular chaperone that plays an important role in cellular proteostasis. Hsp70s are also implicated in the survival and pathogenicity of malaria parasites. The main agent of malaria, Plasmodium falciparum, expresses six Hsp70s. Of these, two (PfHsp70-1 and PfHsp70-z) localize to the parasite cytosol. Previously conducted gene knockout studies suggested that PfHsp70-z is essential, and it has been demonstrated that small-molecule inhibitors targeting PfHsp70-1 cause parasite death. For this reason, both PfHsp70-1 and PfHsp70-z are potential antimalarial targets. Two cyclic lipopeptides, colistin and polymyxin B (PMB), have been shown to bind another heat shock protein, Hsp90, inhibiting its chaperone function. In the current study, we investigated the effect of PMB on the structure-function features of PfHsp70-1 and PfHsp70-z. Using surface plasmon resonance analysis, we observed that PMB directly interacts with both PfHsp70-1 and PfHsp70-z. In addition, using circular dichroism spectrometric analysis combined with tryptophan fluorescence measurements, we observed that PMB modulated the secondary and tertiary structures of Hsp70. Furthermore, PMB inhibited the basal ATPase activity and chaperone function of the two Hsp70s. Our findings suggest that PMB associates with Hsp70 to inhibit its function. In light of the central role of Hsp70 in cellular proteostasis and its essential role in the development of malaria parasites in particular, our findings expand the library of small-molecule inhibitors that target this medically important class of molecular chaperones.

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Section: Discussionmentioning

confidence: 99%

“…It has been proposed that PMB and other cyclic lipopeptide-based antibiotics physically interact with Hsp90 to inhibit its chaperone function (Minagawa et al 2012). However, the effect of PMB on the function of Hsp70 remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Polymyxin B inhibits the chaperone activity of Plasmodium falciparum Hsp70

Zininga

Pooe

Makhado

et al. 2017

Cell Stress and Chaperones

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“… 171 Large cyclic, lipopeptide antibiotics such as polymyxin B ( 10 ), polymyxin B nonapeptide ( 11 ), colistin ( 12 ), and gramicidin S ( 13 ) inhibit chaperone activity of HtpG in the model organism Synechococcus elongatus PCC7942 by binding its N-terminus and inducing oligomerization and/or aggregation. 172 Compounds BI-88B3 ( 14 ) and BI-88D7 ( 15 ) bind the substrate-binding β-domain of the E. coli DnaK, and BI-88B3 ( 14 ) had weak antimicrobial activity against E. coli and Yersinia pseudotuberculosis . 173 N α -[Tetradecanoyl-(4-aminomethylbenzoyl)]- l -isoleucine ( 16 ) inhibits the secondary peptide cis–trans isomerase activity of the E. coli DnaK 174 but has poor antimicrobial activity.…”

Section: Targeting the Proteostasis Network: Chaperones And Their Cofmentioning

confidence: 99%

Targeting the Proteostasis Network for Mycobacterial Drug Discovery

et al. 2018

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the world’s deadliest infectious diseases and urgently requires new antibiotics to treat drug-resistant strains and to decrease the duration of therapy. During infection, Mtb encounters numerous stresses associated with host immunity, including hypoxia, reactive oxygen and nitrogen species, mild acidity, nutrient starvation, and metal sequestration and intoxication. The Mtb proteostasis network, composed of chaperones, proteases, and a eukaryotic-like proteasome, provides protection from stresses and chemistries of host immunity by maintaining the integrity of the mycobacterial proteome. In this Review, we explore the proteostasis network as a noncanonical target for antibacterial drug discovery.

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“…We started the screening of MTH1 inhibitors using chemical array platforms, ultrahigh throughput screening for small-molecule binders of proteins of interest 12 13 14 . Our chemical arrays were used to obtain small-molecule inhibitors of various proteins derived from mammals 15 16 17 18 19 20 21 , fungi 22 , prokaryotes 23 , and viruses 24 25 .…”

mentioning

confidence: 99%

Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival

Kawamura

Kawatani

Muroi

et al. 2016

Sci Rep

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108

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Since recent publications suggested that the survival of cancer cells depends on MTH1 to avoid incorporation of oxidized nucleotides into the cellular DNA, MTH1 has attracted attention as a potential cancer therapeutic target. In this study, we identified new purine-based MTH1 inhibitors by chemical array screening. However, although the MTH1 inhibitors identified in this study targeted cellular MTH1, they exhibited only weak cytotoxicity against cancer cells compared to recently reported first-in-class inhibitors. We performed proteomic profiling to investigate the modes of action by which chemically distinct MTH1 inhibitors induce cancer cell death, and found mechanistic differences among the first-in-class MTH1 inhibitors. In particular, we identified tubulin as the primary target of TH287 and TH588 responsible for the antitumor effects despite the nanomolar MTH1-inhibitory activity in vitro. Furthermore, overexpression of MTH1 did not rescue cells from MTH1 inhibitor–induced cell death, and siRNA-mediated knockdown of MTH1 did not suppress cancer cell growth. Taken together, we conclude that the cytotoxicity of MTH1 inhibitors is attributable to off-target effects and that MTH1 is not essential for cancer cell survival.

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Cyclic lipopeptide antibiotics bind to the N-terminal domain of the prokaryotic Hsp90 to inhibit the chaperone activity

Cited by 22 publications

References 41 publications

Polymyxin B inhibits the chaperone activity of Plasmodium falciparum Hsp70

Polymyxin B inhibits the chaperone activity of Plasmodium falciparum Hsp70

Targeting the Proteostasis Network for Mycobacterial Drug Discovery

Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival

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