A novel application of radiomimetic compounds as antibiotic drugs

Andros, Christina C; Dubay, Ryan; Mitchell, Kayleigh D; Chen, Aaron; Holmes, Dawn E.; Kennedy, Daniel R.

doi:10.1111/jphp.12432

Cited by 7 publications

(5 citation statements)

References 41 publications

(85 reference statements)

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“…In the presence of iron and oxygen, it produces superoxide and hydroxyl radicals that damage DNA and other cellular components. It showed antibacterial activity against several bacteria [94].…”

Section: Radiomimetic Compoundsmentioning

confidence: 99%

Repurposing of Anticancer Drugs for the Treatment of Bacterial Infections

Soo

Kwan

Quezada

et al. 2017

CTMC

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Despite the fact that bacterial infections are one of the leading causes of death worldwide and that mortality rates are increasing at alarming rates, no new antibiotics have been produced by the pharmaceutical industry in more than a decade. The situation is so dire that the World Health Organization warned that we may enter a "post-antibiotic era" within this century; accordingly, bacteria resistant against all known antibiotics are becoming common and already producing untreatable infections. Although several novel approaches to combat bacterial infections have been proposed, they have yet to be implemented in clinical practice. Hence, we propose that a more plausible and faster approach is the utilization of drugs originally developed for other purposes besides antimicrobial activity. Among these are some anticancer molecules proven effective in vitro for eliminating recalcitrant, multidrug tolerant bacteria; some of which also protect animals from infections and recently are undergoing clinical trials. In this review, we highlight the similarities between cancer cells/tumors and bacterial infections, and present evidence that supports the utilization of some anticancer drugs, including 5-fluorouracil (5-FU), gallium (Ga) compounds, and mitomycin C, as antibacterials. Each of these drugs has some promising properties such as broad activity (all three compounds), dual antibiotic and antivirulence properties (5-FU), efficacy against multidrug resistant strains (Ga), and the ability to kill metabolically dormant persister cells which cause chronic infections (mitomycin C).

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Section: Radiomimetic Compoundsmentioning

confidence: 99%

Repurposing of Anticancer Drugs for the Treatment of Bacterial Infections

Soo

Kwan

Quezada

et al. 2017

CTMC

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“…Like other members of the enediyne antitumor antibiotic family such as calicheamicin and neocarzinostatin, LDM exerts extreme cytotoxic potencies by abstracting hydrogen atoms from carbons of the sugar backbone in the minor groove of complementary DNA, leading to double-strand or single-strand breaks of DNA molecules, in the presence of oxygen 38 . The hypoxic microenvironment in solid tumors limits the effects of anti-cancer therapies like ionizing radiation and conventional radiomimetics such as enediynes which need oxygen to cause lethal DNA https://doi.org/10.1038/s41698-024-00584-z breaks 39 . However, LDM can induce inter-strand cross-links of DNA instead of DNA breaks in the hypoxic tumor microenvironment; this unique mechanism of action makes it nearly three-fold more cytotoxic to hypoxic than to normoxic cells 40 .…”

Section: Discussionmentioning

confidence: 99%

A new TROP2-targeting antibody-drug conjugate shows potent antitumor efficacy in breast and lung cancers

Zhou,

Zhai,

Zhang

et al. 2024

npj Precis. Onc.

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Trophoblast cell surface antigen 2 (Trop2) is considered to be an attractive therapeutic target in cancer treatments. We previously generated a new humanized anti-Trop2 antibody named hIMB1636, and designated it as an ideal targeting carrier for cancer therapy. Lidamycin (LDM) is a new antitumor antibiotic, containing an active enediyne chromophore (AE) and a noncovalently bound apoprotein (LDP). AE and LDP can be separated and reassembled, and the reassembled LDM possesses cytotoxicity similar to that of native LDM; this has made LDM attractive in the preparation of gene-engineering drugs. We herein firstly prepared a new fusion protein hIMB1636-LDP composed of hIMB1636 and LDP by genetic engineering. This construct showed potent binding activities to recombinant antigen with a KD value of 4.57 nM, exhibited binding to Trop2-positive cancer cells and internalization and transport to lysosomes, and demonstrated powerful tumor-targeting ability in vivo. We then obtained the antibody-drug conjugate (ADC) hIMB1636-LDP-AE by molecular reconstitution. In vitro, hIMB1636-LDP-AE inhibited the proliferation, migration, and tumorsphere formation of tumor cells with half-maximal inhibitory concentration (IC50) values at the sub-nanomolar level. Mechanistically, hIMB1636-LDP-AE induced apoptosis and cell-cycle arrest. In vivo, hIMB1636-LDP-AE also inhibited the growth of breast and lung cancers in xenograft models. Moreover, compared to sacituzumab govitecan, hIMB1636-LDP-AE showed more potent antitumor activity and significantly lower myelotoxicity in tumors with moderate Trop2 expression. This study fully revealed the potent antitumor efficacy of hIMB1636-LDP-AE, and also provided a new preparation method for LDM-based ADC, as well as a promising candidate for breast cancer and lung cancer therapeutics.

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“…59 Calicheamicin is extremely toxic to all cells and, 51 Gates 1999: 497. 52 Andros et al 2015Andros et al : 1377 Andros et al 2015: 1377. 54 Lown 1983 Andros et al 2015Andros et al : 1372 Cafferty et al 2020: 139.…”

Section: Tumour and Autoimmune Therapymentioning

confidence: 99%

“…52 Andros et al 2015Andros et al : 1377 Andros et al 2015: 1377. 54 Lown 1983 Andros et al 2015Andros et al : 1372 Cafferty et al 2020: 139. 57 Groselj et al 2018: 120.…”

Section: Tumour and Autoimmune Therapymentioning

confidence: 99%

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Mechanism of Action and Use of Radiomimetic Compounds (Part 2)

Deli

2023

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Radiomimetic compounds, similarly to ionising radiation can directly or indirectly cause DNA damage. Two major groups of these compounds, alkylating agents and antimetabolites, have already been discussed in the first part of this article. The topic of this article is an overview of radiomimetic substances of biological origin; they are grouped and discussed upon their chemical structure. Some bacteria, belonging to the class of Actinobacteria can produce compounds with radiomimetic property as part of their defence mechanisms, such as bleomycins, enediynes, streptonigrins, etc. Radiomimetic compounds of bacterial origin can be divided into three main groups: radiomimetic glycopeptides, enediynes and quinone antibiotics. Each of them induces double-strand DNA breaks. Some of them work through their reactive radicals and the molecules are also transformed when they break DNA. Others, such as bleomycin and similar glycopeptides, have an enzyme-like catalytic effect as the molecule regenerates itself after interacting with DNA thus the same molecule can create new DNA breaks again. The damage caused by radiation and by bleomycin is very similar: double DNA strand breaks occur in close proximity to each other, below the lethal dose of the cell, so as the cell does not die, the DNA repair process is activated, which can lead to the formation of dicentric chromosomes and other detectable DNA alterations. This review briefly summarises the mechanism of action of bacterial radiomimetic compounds and their benefit.

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A novel application of radiomimetic compounds as antibiotic drugs

Abstract: Radiomimetic compounds have activity against a wide variety of microorganisms and would support the development of radiomimetic-antibody conjugates as potential antibiotics as an option against severe bacterial infections.

Cited by 7 publications

References 41 publications

Repurposing of Anticancer Drugs for the Treatment of Bacterial Infections

Repurposing of Anticancer Drugs for the Treatment of Bacterial Infections

A new TROP2-targeting antibody-drug conjugate shows potent antitumor efficacy in breast and lung cancers

Mechanism of Action and Use of Radiomimetic Compounds (Part 2)

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