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Antivirulence Strategies to Overcome Antimicrobial Resistance

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (30 May 2023) | Viewed by 8624

Special Issue Editor

Special Issue Information

Dear Colleagues,

The spread of antimicrobial resistance (AMR) has become a major threat to global health and healthcare systems, causing at least 700 000 deaths/year worldwide, and this figure is estimated to reach 10 million by 2050 if no effective actions are taken. This situation is also likely to worsen as a consequences of the COVID-19 pandemic, due to the extensive use of antimicrobials in COVID-19 cotreatment, as well as the interruption of treatments and slowing down of monitoring programs due to lockdown measures.

The main cause of AMR diffusion is likely the misuse and overuse of antimicrobial agents in healthcare settings, agriculture, and livestock; thus, it is necessary to move towards a common objective of the appropriate use of antimicrobials and to promote the research of new alternative approaches.

Antivirulence therapy represents an increasingly interesting alternative strategy against AMR, as this approach aims to target pathways required for pathogenesis, which are not essential for microbial growth. Through this method of aiming to prevent host infection rather than killing pathogens, antivirulence compounds do not exert selective pressure, thus reducing the risk of insurgence of resistance.

This Special Issue will focus on the recent research advances in antivirulence and targeted strategies of hosts against bacterial, viral, or fungal infections. Authors are welcome to contribute original research articles and reviews that align with the topic of this Special Issue.

Dr. Chiarelli Laurent
Guest Editor

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Keywords

  • antimicrobial agents
  • antimicrobial resistance
  • virulence factors
  • virulence determinants
  • biofilm
  • anti-virulence drugs
  • quorum sensing inhibitors
  • host-directed therapy

Published Papers (4 papers)

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Research

16 pages, 12512 KiB  
Article
Anti-Virulence Strategy of Novel Dehydroabietic Acid Derivatives: Design, Synthesis, and Antibacterial Evaluation
by Puying Qi, Na Wang, Taihong Zhang, Yumei Feng, Xiang Zhou, Dan Zeng, Jiao Meng, Liwei Liu, Linhong Jin and Song Yang
Int. J. Mol. Sci. 2023, 24(3), 2897; https://doi.org/10.3390/ijms24032897 - 02 Feb 2023
Cited by 8 | Viewed by 1719
Abstract
Anti-virulence strategies are attractive and interesting strategies for controlling bacterial diseases because virulence factors are fundamental to the infection process of numerous serious phytopathogenics. To extend the novel anti-virulence agents, a series of dehydroabietic acid (DAA) derivatives decorated with amino alcohol unit were [...] Read more.
Anti-virulence strategies are attractive and interesting strategies for controlling bacterial diseases because virulence factors are fundamental to the infection process of numerous serious phytopathogenics. To extend the novel anti-virulence agents, a series of dehydroabietic acid (DAA) derivatives decorated with amino alcohol unit were semi-synthesized based on structural modification of the renewable natural DAA and evaluated for their antibacterial activity against Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas axonopodis pv. citri (Xac), and Pseudomonas syringae pv. actinidiae (Psa). Compound 2b showed the most promising antibacterial activity against Xoo with an EC50 of 2.7 μg mL−1. Furthermore, compound 2b demonstrated remarkable control effectiveness against bacterial leaf blight (BLB) in rice, with values of 48.6% and 61.4% for curative and protective activities. In addition, antibacterial behavior suggested that compound 2b could suppress various virulence factors, including EPS, biofilm, swimming motility, and flagella. Therefore, the current study provided promising lead compounds for novel bactericides discovery by inhibiting bacterial virulence factors. Full article
(This article belongs to the Special Issue Antivirulence Strategies to Overcome Antimicrobial Resistance)
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14 pages, 1773 KiB  
Article
Identification of Compounds Preventing A. fumigatus Biofilm Formation by Inhibition of the Galactosaminogalactan Deacetylase Agd3
by Carla I. I. Seegers, Danielle J. Lee, Patricia Zarnovican, Susanne H. Kirsch, Rolf Müller, Thomas Haselhorst and Françoise H. Routier
Int. J. Mol. Sci. 2023, 24(3), 1851; https://doi.org/10.3390/ijms24031851 - 17 Jan 2023
Cited by 2 | Viewed by 2648
Abstract
The opportunistic fungus Aspergillus fumigatus causes a set of diseases ranging from allergy to lethal invasive mycosis. Within the human airways, A. fumigatus is embedded in a biofilm that forms not only a barrier against the host immune defense system, but also creates [...] Read more.
The opportunistic fungus Aspergillus fumigatus causes a set of diseases ranging from allergy to lethal invasive mycosis. Within the human airways, A. fumigatus is embedded in a biofilm that forms not only a barrier against the host immune defense system, but also creates a physical barrier protecting the fungi from chemicals such as antifungal drugs. Novel therapeutic strategies aim at combining drugs that inhibit biofilm synthesis or disrupt existing biofilm with classical antimicrobials. One of the major constituents of A. fumigatus biofilm is the polysaccharide galactosaminogalactan (GAG) composed of α1,4-linked N-acetylgalactosamine, galactosamine, and galactose residues. GAG is synthesized on the cytosolic face of the plasma membrane and is extruded in the extracellular space, where it is partially deacetylated. The deacetylase Agd3 that mediates this last step is essential for the biofilm formation and full virulence of the fungus. In this work, a previously described enzyme-linked lectin assay, based on the adhesion of deacetylated GAG to negatively charged plates and quantification with biotinylated soybean agglutinin was adapted to screen microbial natural compounds, as well as compounds identified in in silico screening of drug libraries. Actinomycin X2, actinomycin D, rifaximin, and imatinib were shown to inhibit Agd3 activity in vitro. At a concentration of 100 µM, actinomycin D and imatinib showed a clear reduction in the biofilm biomass without affecting the fungal growth. Finally, imatinib reduced the virulence of A. fumigatus in a Galleria mellonella infection model in an Agd3-dependent manner. Full article
(This article belongs to the Special Issue Antivirulence Strategies to Overcome Antimicrobial Resistance)
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11 pages, 1548 KiB  
Article
Targeting Virulence Genes Expression in Vibrio vulnificus by Alternative Carbon Sources
by Aldo Nicosia, Monica Salamone and Marcello Tagliavia
Int. J. Mol. Sci. 2022, 23(23), 15278; https://doi.org/10.3390/ijms232315278 - 03 Dec 2022
Viewed by 1374
Abstract
Vibrio vulnificus is an opportunistic human pathogen causing self-limiting gastroenteritis, life-threatening necrotizing soft tissue infection, and fulminating septicaemia. An increasing rate of infections has been reported worldwide, characterized by sudden onset of sepsis and/or rapid progression to irreversible tissue damage or death. Timely [...] Read more.
Vibrio vulnificus is an opportunistic human pathogen causing self-limiting gastroenteritis, life-threatening necrotizing soft tissue infection, and fulminating septicaemia. An increasing rate of infections has been reported worldwide, characterized by sudden onset of sepsis and/or rapid progression to irreversible tissue damage or death. Timely intervention is essential to control the infection, and it is based on antibiotic therapy, which does not always result in the effective and rapid blocking of virulence. Inhibitors of essential virulence regulators have been reported in the last years, but none of them has been further developed, so far. We aimed to investigate whether exposure to some carbon compounds, mostly easily metabolizable, could result in transcriptional down-regulation of virulence genes. We screened various carbon sources already available for human use (thus potentially easy to be repurposed), finding some of them (including mannitol and glycerol) highly effective in down-regulating, in vitro and ex-vivo, the mRNA levels of several relevant -even essential- virulence factors (hlyU, lrp, rtxA, vvpE, vvhA, plpA, among others). This paves the way for further investigations aiming at their development as virulence inhibitors and to unveil mechanisms explaining such observed effects. Moreover, data suggesting the existence of additional regulatory networks of some virulence genes are reported. Full article
(This article belongs to the Special Issue Antivirulence Strategies to Overcome Antimicrobial Resistance)
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16 pages, 5400 KiB  
Article
Novel Antibiofilm Inhibitor Ginkgetin as an Antibacterial Synergist against Escherichia coli
by Yubin Bai, Weiwei Wang, Mengyan Shi, Xiaojuan Wei, Xuzheng Zhou, Bing Li and Jiyu Zhang
Int. J. Mol. Sci. 2022, 23(15), 8809; https://doi.org/10.3390/ijms23158809 - 08 Aug 2022
Cited by 9 | Viewed by 2381
Abstract
As an opportunistic pathogen, Escherichia coli (E. coli) forms biofilm that increases the virulence of bacteria and antibiotic resistance, posing a serious threat to human and animal health. Recently, ginkgetin (Gin) has been discovered to have antiinflammatory, antioxidant, and antitumor properties. In [...] Read more.
As an opportunistic pathogen, Escherichia coli (E. coli) forms biofilm that increases the virulence of bacteria and antibiotic resistance, posing a serious threat to human and animal health. Recently, ginkgetin (Gin) has been discovered to have antiinflammatory, antioxidant, and antitumor properties. In the present study, we evaluated the antibiofilm and antibacterial synergist of Gin against E. coli. Additionally, Alamar Blue assay combined with confocal laser scanning microscope (CLSM) and crystal violet (CV) staining was used to evaluate the effect of antibiofilm and antibacterial synergist against E. coli. Results showed that Gin reduces biofilm formation, exopolysaccharide (EPS) production, and motility against E. coli without limiting its growth and metabolic activity. Furthermore, we identified the inhibitory effect of Gin on AI-2 signaling molecule production, which showed apparent anti-quorum sensing (QS) properties. The qRT-PCR also indicated that Gin reduced the transcription of curli-related genes (csgA, csgD), flagella-formation genes (flhC, flhD, fliC, fliM), and QS-related genes (luxS, lsrB, lsrK, lsrR). Moreover, Gin showed obvious antibacterial synergism to overcome antibiotic resistance in E. coli with marketed antibiotics, including gentamicin, colistin B, and colistin E. These results suggested the potent antibiofilm and novel antibacterial synergist effect of Gin for treating E. coli infections. Full article
(This article belongs to the Special Issue Antivirulence Strategies to Overcome Antimicrobial Resistance)
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