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Article: Transcriptomic interplay between

Kho, Zhi Ying / Azad, Mohammad Abul Kalam / Zhu, Yan / Han, Mei-Ling / Zhou, Qi Tony / Velkov, Tony / Naderer, Thomas / Li, Jian

bioRxiv : the preprint server for biology

2024

Abstract: Optimization of antibiotic therapy has been hindered by our dearth of understanding on the mechanism of the host-pathogen-drug interactions. Here, we employed dual RNA-sequencing to examine transcriptomic perturbations in response to polymyxin B in a co- ... ...

Abstract	Optimization of antibiotic therapy has been hindered by our dearth of understanding on the mechanism of the host-pathogen-drug interactions. Here, we employed dual RNA-sequencing to examine transcriptomic perturbations in response to polymyxin B in a co-culture infection model of Importance: In the context of the development of bacterial resistance during the course of antibiotic therapy, the role of macrophages in shaping bacterial response to antibiotic killing remains enigmatic. Herein we employed dual RNA-sequencing and an
Language	English
Publishing date	2024-01-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.23.576770
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Article: Bifunctional antibiotic hybrids: A review of clinical candidates.

Koh, Augustine Jing Jie / Thombare, Varsha / Hussein, Maytham / Rao, Gauri G / Li, Jian / Velkov, Tony

Frontiers in pharmacology

2023 Volume 14, Page(s) 1158152

Abstract: Antibiotic resistance is a top threat to human health and a priority across the globe. This problematic issue is accompanied by the decline of new antibiotics in the pipeline over the past 30 years. In this context, an urgent need to develop new ... ...

Abstract	Antibiotic resistance is a top threat to human health and a priority across the globe. This problematic issue is accompanied by the decline of new antibiotics in the pipeline over the past 30 years. In this context, an urgent need to develop new strategies to combat antimicrobial resistance is in great demand. Lately, among the possible approaches used to deal with antimicrobial resistance is the covalent ligation of two antibiotic pharmacophores that target the bacterial cells through a dissimilar mode of action into a single hybrid molecule, namely hybrid antibiotics. This strategy exhibits several advantages, including better antibacterial activity, overcoming the existing resistance towards individual antibiotics, and may ultimately delay the onset of bacterial resistance. This review sheds light on the latest development of the dual antibiotic hybrids pipeline, their potential mechanisms of action, and challenges in their use.
Language	English
Publishing date	2023-06-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2023.1158152
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Polymyxins: Mode of Action.

Li, Zhifeng / Velkov, Tony

Advances in experimental medicine and biology

2019 Volume 1145, Page(s) 37–54

Abstract: The dry antibiotic development pipeline coupled with the emergence of multi-drug resistant Gram-negative 'superbugs' has driven the revival of the polymyxin lipopeptide antibiotics. Understanding the mode of action of antibiotics is an important ... ...

Abstract	The dry antibiotic development pipeline coupled with the emergence of multi-drug resistant Gram-negative 'superbugs' has driven the revival of the polymyxin lipopeptide antibiotics. Understanding the mode of action of antibiotics is an important precursor for optimizing their use and development. This chapter provides a concise treatise of the current knowledge-based on the primary mode of action of polymyxins as well as recent developments in understanding of bacterial cell responses and secondary modes of action.
MeSH term(s)	Anti-Bacterial Agents/pharmacology ; Gram-Negative Bacteria/drug effects ; Polymyxins/pharmacology
Chemical Substances	Anti-Bacterial Agents ; Polymyxins
Language	English
Publishing date	2019-07-30
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-16373-0_4
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Article: Discovery of Novel Polymyxin-Like Antibiotics.

Velkov, Tony / Roberts, Kade D

Advances in experimental medicine and biology

2019 Volume 1145, Page(s) 343–362

Abstract: The antimicrobial lipopeptides polymyxin B and colistin (polymyxin E) are used as a 'last-line' therapy for infections caused by multidrug-resistant (MDR) Gram-negative pathogens. However, their effective use as antibiotic drugs in the clinical setting ... ...

Abstract	The antimicrobial lipopeptides polymyxin B and colistin (polymyxin E) are used as a 'last-line' therapy for infections caused by multidrug-resistant (MDR) Gram-negative pathogens. However, their effective use as antibiotic drugs in the clinical setting is still plagued by significant toxicity issues, in particular their potential for nephrotoxicity. Furthermore, resistance to the polymyxins has begun to emerge in the clinic, which implies a total lack of antibiotics for the treatment of life-threatening infections caused by the Gram-negative 'superbugs'. This chapter details our current understanding of polymyxin structure-activity relationships as well as recent pre-clinical and clinical drug development efforts aimed at generating new polymyxin antibiotics with improved safety and efficacy.
MeSH term(s)	Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Drug Discovery ; Polymyxins/chemistry ; Polymyxins/pharmacology ; Structure-Activity Relationship
Chemical Substances	Anti-Bacterial Agents ; Polymyxins
Language	English
Publishing date	2019-07-30
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-16373-0_20
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Article: Interactions between Human Liver Fatty Acid Binding Protein and Peroxisome Proliferator Activated Receptor Selective Drugs.

Velkov, Tony

PPAR research

2013 Volume 2013, Page(s) 938401

Abstract: Fatty acid binding proteins (FABPs) act as intracellular shuttles for fatty acids as well as lipophilic xenobiotics to the nucleus, where these ligands are released to a group of nuclear receptors called the peroxisome proliferator activated receptors ( ... ...

Abstract	Fatty acid binding proteins (FABPs) act as intracellular shuttles for fatty acids as well as lipophilic xenobiotics to the nucleus, where these ligands are released to a group of nuclear receptors called the peroxisome proliferator activated receptors (PPARs). PPAR mediated gene activation is ultimately involved in maintenance of cellular homeostasis through the transcriptional regulation of metabolic enzymes and transporters that target the activating ligand. Here we show that liver- (L-) FABP displays a high binding affinity for PPAR subtype selective drugs. NMR chemical shift perturbation mapping and proteolytic protection experiments show that the binding of the PPAR subtype selective drugs produces conformational changes that stabilize the portal region of L-FABP. NMR chemical shift perturbation studies also revealed that L-FABP can form a complex with the PPAR ligand binding domain (LBD) of PPAR α . This protein-protein interaction may represent a mechanism for facilitating the activation of PPAR transcriptional activity via the direct channeling of ligands between the binding pocket of L-FABP and the PPAR α LBD. The role of L-FABP in the delivery of ligands directly to PPAR α via this channeling mechanism has important implications for regulatory pathways that mediate xenobiotic responses and host protection in tissues such as the small intestine and the liver where L-FABP is highly expressed.
Language	English
Publishing date	2013-02-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2237981-2
ISSN	1687-4765 ; 1687-4757
ISSN (online)	1687-4765
ISSN	1687-4757
DOI	10.1155/2013/938401
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Article ; Online: The specificity of the influenza B virus hemagglutinin receptor binding pocket: what does it bind to?

Velkov, Tony

Journal of molecular recognition : JMR

2013 Volume 26, Issue 10, Page(s) 439–449

Abstract: The influenza surface glycoprotein hemagglutinin (HA) binds to sialylglycoproteins and sialylglycolipids on the surface of host cells. These sialyl-glycans, usually linked to galactose in either α2,6 or α2,3 configurations, are the receptors for the ... ...

Abstract	The influenza surface glycoprotein hemagglutinin (HA) binds to sialylglycoproteins and sialylglycolipids on the surface of host cells. These sialyl-glycans, usually linked to galactose in either α2,6 or α2,3 configurations, are the receptors for the viral HA, the binding to which promotes viral attachment, membrane fusion, and internalization of the virus. This review examines all of the available receptor binding data on the influenza B HA and provides a structure recognition perspective for the receptor binding preferences of influenza B virus HA regional and egg-adapted variants. Overall, the review serves as an up-to-date compendium of the literature binding data, and the presented discussions assist the reader in reaching a consensus understanding of the receptor specificity determinants for the influenza B HA.
MeSH term(s)	Animals ; Binding Sites ; Chickens ; Dogs ; Eggs/virology ; Glycolipids/chemistry ; Glycolipids/metabolism ; Hemagglutinin Glycoproteins, Influenza Virus/chemistry ; Hemagglutinin Glycoproteins, Influenza Virus/metabolism ; Humans ; Influenza B virus/chemistry ; Influenza B virus/growth & development ; Influenza B virus/metabolism ; Madin Darby Canine Kidney Cells ; Molecular Docking Simulation ; Protein Binding ; Receptors, Virus/chemistry ; Receptors, Virus/metabolism ; Sialoglycoproteins/chemistry ; Sialoglycoproteins/metabolism
Chemical Substances	Glycolipids ; Hemagglutinin Glycoproteins, Influenza Virus ; Receptors, Virus ; Sialoglycoproteins ; sialoglycolipids
Language	English
Publishing date	2013-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1015084-5
ISSN	1099-1352 ; 0952-3499
ISSN (online)	1099-1352
ISSN	0952-3499
DOI	10.1002/jmr.2293
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Article ; Online: Rescuing the Last-Line Polymyxins: Achievements and Challenges.

Nang, Sue C / Azad, Mohammad A K / Velkov, Tony / Zhou, Qi Tony / Li, Jian

Pharmacological reviews

2021 Volume 73, Issue 2, Page(s) 679–728

Abstract: Antibiotic resistance is a major global health challenge and, worryingly, several key Gram negative pathogens can become resistant to most currently available antibiotics. Polymyxins have been revived as a last-line therapeutic option for the treatment ... ...

Abstract	Antibiotic resistance is a major global health challenge and, worryingly, several key Gram negative pathogens can become resistant to most currently available antibiotics. Polymyxins have been revived as a last-line therapeutic option for the treatment of infections caused by multidrug-resistant Gram negative bacteria, in particular
MeSH term(s)	Anti-Bacterial Agents/adverse effects ; Colistin/adverse effects ; Drug Resistance, Multiple, Bacterial ; Gram-Negative Bacterial Infections/drug therapy ; Humans ; Polymyxin B ; Polymyxins/adverse effects
Chemical Substances	Anti-Bacterial Agents ; Polymyxins ; Polymyxin B (J2VZ07J96K) ; Colistin (Z67X93HJG1)
Language	English
Publishing date	2021-01-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	209898-2
ISSN	1521-0081 ; 0031-6997
ISSN (online)	1521-0081
ISSN	0031-6997
DOI	10.1124/pharmrev.120.000020
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Article ; Online: Fe

Xu, Yuliang / Wang, Sihan / Xiong, Jincheng / Zheng, Pimiao / Zhang, Huixia / Chen, Shiqi / Ma, Qiang / Shen, Jianzhong / Velkov, Tony / Dai, Chongshan / Jiang, Haiyang

Advanced healthcare materials

2024 , Page(s) e2303839

Abstract: Metal-organic framework (MOF)-based drug delivery nanomaterials for cancer therapy have attracted increasing attention in recent years. Here, an enhanced chemodynamic anti-tumor therapy strategy by promoting the Fenton reaction by using core-shell ... ...

Abstract	Metal-organic framework (MOF)-based drug delivery nanomaterials for cancer therapy have attracted increasing attention in recent years. Here, an enhanced chemodynamic anti-tumor therapy strategy by promoting the Fenton reaction by using core-shell zeolitic imidazolate framework-8 (ZIF-8)@Fe
Language	English
Publishing date	2024-02-09
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2649576-4
ISSN	2192-2659 ; 2192-2640
ISSN (online)	2192-2659
ISSN	2192-2640
DOI	10.1002/adhm.202303839
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Article ; Online: The antihelminth drug rafoxanide reverses chromosomal-mediated colistin-resistance in

Han, Rongjia / Xing, Jiabao / Sun, Huarun / Guo, Zeyu / Yi, Kaifang / Hu, Gongzheng / Zhai, Yajun / Velkov, Tony / Wu, Hua

mSphere

2023 Volume 8, Issue 5, Page(s) e0023423

Abstract: The emergence and rapid spread of multi-drug-resistant (MDR) bacteria pose a serious threat to global healthcare. Although the synergistic effect of rafoxanide and colistin was reported, little is known regarding the potential mechanism of this synergy, ... ...

Abstract	The emergence and rapid spread of multi-drug-resistant (MDR) bacteria pose a serious threat to global healthcare. Although the synergistic effect of rafoxanide and colistin was reported, little is known regarding the potential mechanism of this synergy, particularly against chromosomal-mediated colistin-resistant
MeSH term(s)	Humans ; Animals ; Swine ; Colistin/pharmacology ; Rafoxanide/pharmacology ; Klebsiella pneumoniae ; Reactive Oxygen Species ; Chromosomes ; Adenosine Triphosphate
Chemical Substances	Colistin (Z67X93HJG1) ; Rafoxanide (22F4FLA7DH) ; Reactive Oxygen Species ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2023-09-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2379-5042
ISSN (online)	2379-5042
DOI	10.1128/msphere.00234-23
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Article ; Online: Interactions between Human Liver Fatty Acid Binding Protein and Peroxisome Proliferator Activated Receptor Selective Drugs

Tony Velkov

PPAR Research, Vol

2013 Volume 2013

Abstract	Fatty acid binding proteins (FABPs) act as intracellular shuttles for fatty acids as well as lipophilic xenobiotics to the nucleus, where these ligands are released to a group of nuclear receptors called the peroxisome proliferator activated receptors (PPARs). PPAR mediated gene activation is ultimately involved in maintenance of cellular homeostasis through the transcriptional regulation of metabolic enzymes and transporters that target the activating ligand. Here we show that liver- (L-) FABP displays a high binding affinity for PPAR subtype selective drugs. NMR chemical shift perturbation mapping and proteolytic protection experiments show that the binding of the PPAR subtype selective drugs produces conformational changes that stabilize the portal region of L-FABP. NMR chemical shift perturbation studies also revealed that L-FABP can form a complex with the PPAR ligand binding domain (LBD) of PPARα. This protein-protein interaction may represent a mechanism for facilitating the activation of PPAR transcriptional activity via the direct channeling of ligands between the binding pocket of L-FABP and the PPARαLBD. The role of L-FABP in the delivery of ligands directly to PPARα via this channeling mechanism has important implications for regulatory pathways that mediate xenobiotic responses and host protection in tissues such as the small intestine and the liver where L-FABP is highly expressed.
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Hindawi Limited
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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