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Molecules
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Different Strategies to Overcome Multi-Drug Resistant and Persistent Infectious Diseases
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Different Strategies to Overcome Multi-Drug Resistant and Persistent Infectious Diseases

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 5895

Special Issue Editors

Dr. Simone Di Micco

E-Mail Website
Guest Editor
European Biomedical Research Institute of Salerno (EBRIS), Via De Renzi, 50, 84125 Salerno, Italy
Interests: NMR spectroscopy; molecular docking; qunatum mechanics; homology modeling; molecular dynamics; drug discovery; configurational and conformational determination
Dr. Simona Musella

E-Mail Website
Guest Editor
European Biomedical Research Institute of Salerno (EBRIS), Via Salvatore De Renzi 50, 84125 Salerno, Italy
Interests: heterocyclic chemistry; solid phase synthesis; combinatorial synthesis; drug design; drug discovery

Special Issue Information

Dear Colleagues,

The continuous efforts of scientists from diverse fields is necessary not only to better understand the mechanism underlying multidrug resistance (MDR) in cancer and infectious diseases but also to boost the development of new strategies to fight MDR phenotypes.

Chemotherapy is still a main option for cancer treatment, but its efficacy is often limited not only by side effects but also by multidrug resistance. Multiple mechanisms of tumor resistance have been explored that can be grouped into: a) overexpression of ATP-binding cassette pumps (e.g., P-glycoprotein, P-gp); b) defective apoptotic mechanisms; c) structural alterations of the drug targets; d) repair of the damaged DNA; and e) detoxicity of the drugs by certain enzymes. In addition to these changes at the molecular level, the tumor microenvironment also plays key roles in the development of MDR.

A better understanding of the mechanisms of MDR and targets of novel chemotherapy agents should provide guidance for future research concerning new effective strategies in cancer treatment.

Nowadays, antibiotic resistance is one of the greatest challenges in drug discovery, representing a serious problem for public health. Globalization, excessive use of antibiotics in animal husbandry and aquaculture, use of multiple broad-spectrum agents, and lack of good antimicrobial stewardship can be listed as the factors most responsible for the spread of antibiotic resistance. This raises the need to search for alternative methods of controlling antibiotic-resistant pathogens.

This Special Issue aims to gather relevant and innovative research in the field of multidrug resistance and drug development. Both original research articles and reviews are welcome for submission. Areas to be covered in this area may include, but are not limited to: structural biology; biochemistry; synthetic strategies for novel therapeutics; computational biology approaches; development of biophysical screening methods; drug repurposing; and metabolomic and/or proteomic analysis.

Dr. Simone Di Micco
Dr. Simona Musella
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cancer
  • Multi Drug Resistance
  • Chemotherapeutics
  • Drug Repurposing
  • infectious disease
  • Drug Discovery
  • Multifactorial Disease
  • Antimicrobial Agents

Published Papers (3 papers)

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Research

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15 pages, 3957 KiB  
Article
Early Molecular Insights into Thanatin Analogues Binding to A. baumannii LptA
by Kathryn K. Oi, Kerstin Moehle, Matthias Schuster and Oliver Zerbe
Molecules 2023, 28(11), 4335; https://doi.org/10.3390/molecules28114335 - 25 May 2023
Cited by 1 | Viewed by 1032
Abstract
The cationic antimicrobial ß-hairpin, thanatin, was recently developed into drug-like analogues active against carbapenem-resistant Enterobacteriaceae (CRE). The analogues represent new antibiotics with a novel mode of action targeting LptA in the periplasm and disrupting LPS transport. The compounds lose antimicrobial efficacy when the [...] Read more.
The cationic antimicrobial ß-hairpin, thanatin, was recently developed into drug-like analogues active against carbapenem-resistant Enterobacteriaceae (CRE). The analogues represent new antibiotics with a novel mode of action targeting LptA in the periplasm and disrupting LPS transport. The compounds lose antimicrobial efficacy when the sequence identity to E. coli LptA falls below 70%. We wanted to test the thanatin analogues against LptA of a phylogenetic distant organism and investigate the molecular determinants of inactivity. Acinetobacter baumannii (A. baumannii) is a critical Gram-negative pathogen that has gained increasing attention for its multi-drug resistance and hospital burden. A. baumannii LptA shares 28% sequence identity with E. coli LptA and displays an intrinsic resistance to thanatin and thanatin analogues (MIC values > 32 µg/mL) through a mechanism not yet described. We investigated the inactivity further and discovered that these CRE-optimized derivatives can bind to LptA of A. baumannii in vitro, despite the high MIC values. Herein, we present a high-resolution structure of A. baumannii LptAm in complex with a thanatin derivative 7 and binding affinities of selected thanatin derivatives. Together, these data offer structural insights into why thanatin derivatives are inactive against A. baumannii LptA, despite binding events in vitro. Full article
(This article belongs to the Special Issue Different Strategies to Overcome Multi-Drug Resistant and Persistent Infectious Diseases)
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16 pages, 7155 KiB  
Article
Inosine and D-Mannose Secreted by Drug-Resistant Klebsiella pneumoniae Affect Viability of Lung Epithelial Cells
by Yuhan Zhang, Ziwei Zhou, Wenxuan Xiao, Yuting Tang, Wei Guan, Jiang Wang, Farui Shu, Jiaqi Shen, Shaoyan Gu, Lu Zhang, Qingzhong Wang and Lixin Xie
Molecules 2022, 27(9), 2994; https://doi.org/10.3390/molecules27092994 - 06 May 2022
Cited by 1 | Viewed by 2000
Abstract
The antibiotic resistance rates of Klebsiella pneumoniae have been steadily increasing in recent years. Nevertheless, the metabolic features of the drug-resistant Klebsiella pneumoniae and its associated benefits for bacterial pathogenicity are far from expounded. This study aims to unravel the unique physiological and [...] Read more.
The antibiotic resistance rates of Klebsiella pneumoniae have been steadily increasing in recent years. Nevertheless, the metabolic features of the drug-resistant Klebsiella pneumoniae and its associated benefits for bacterial pathogenicity are far from expounded. This study aims to unravel the unique physiological and metabolic properties specific to drug-resistant K. pneumoniae. Using scanning electron microscopy (SEM), we observed a thicker extracellular mucus layer around a drug-resistant K. pneumonia strain (Kp-R) than a drug-sensitive K. pneumonia strain (Kp-S). Kp-R also produced more capsular polysaccharide (CPS) and biofilm, and appeared to have a significant competitive advantage when co-cultured with Kp-S. Moreover, Kp-R was easier to adhere to and invade A549 epithelial cells than Kp-S but caused less cell-viability damage according to cell counting kit-8 (CCK-8) tests. Immunofluorescence revealed that both Kp-R and Kp-S infection destroyed the tight junctions and F-actin of epithelial cells, while the damage caused by Kp-S was more severe than Kp-R. We detected the extracellular metabolites secreted by the two strains with UHPLC-Q-TOF MS to explore the critical secretion products. We identified 16 predominant compounds that were differentially expressed. Among them, inosine increased the viability of epithelial cells in a dose-dependent manner, and an A2AR antagonist can abolish such enhancement. D-mannose, which was secreted less in Kp-R, inhibited the viability of A549 cells in the range of low doses. These findings provide potential targets and research strategies for preventing and treating drug-resistant K. pneumoniae infections. Full article
(This article belongs to the Special Issue Different Strategies to Overcome Multi-Drug Resistant and Persistent Infectious Diseases)
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Review

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27 pages, 685 KiB  
Review
Drug Resistance: The Role of Exosomal miRNA in the Microenvironment of Hematopoietic Tumors
by Mariaconcetta Cariello, Angela Squilla, Martina Piacente, Giorgia Venutolo and Alessio Fasano
Molecules 2023, 28(1), 116; https://doi.org/10.3390/molecules28010116 - 23 Dec 2022
Cited by 5 | Viewed by 2216
Abstract
Extracellular vesicles (EVs), including exosomes, have an important role thanks to their ability to communicate and exchange information between tumor cells and the tumor microenvironment (TME), and have also been associated with communicating anti-cancer drug resistance (DR). The increase in proliferation of cancer [...] Read more.
Extracellular vesicles (EVs), including exosomes, have an important role thanks to their ability to communicate and exchange information between tumor cells and the tumor microenvironment (TME), and have also been associated with communicating anti-cancer drug resistance (DR). The increase in proliferation of cancer cells alters oxygen levels, which causes hypoxia and results in a release of exosomes by the cancer cells. In this review, the results of studies examining the role of exosomal miRNA in DR, and their mechanism, are discussed in detail in hematological tumors: leukemia, lymphoma, and multiple myeloma. In conclusion, we underline the exosome’s function as a possible drug delivery vehicle by understanding its cargo. Engineered exosomes can be used to be more specific for personalized therapy. Full article
(This article belongs to the Special Issue Different Strategies to Overcome Multi-Drug Resistant and Persistent Infectious Diseases)
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