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Microorganisms
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Anti-virulence Strategies against Microbial Pathogens
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Anti-virulence Strategies against Microbial Pathogens

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Antimicrobial Agents and Resistance".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 18002

Special Issue Editors

Dr. Giuseppantonio Maisetta

E-Mail Website
Guest Editor
Department of Translational Research and New technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
Interests: bacteria; pathogens; biofilm; bacterial virulence; persisters; antimicrobial peptides; antibiotics
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Giovanna Batoni

E-Mail Website1 Website2
Co-Guest Editor
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
Interests: antimicrobial peptides; biofilm infections; unconventional antimicrobials; wound infections; pulmonary infections; host response to infections; Pseudomonas aeruginosa; Mycobacterium tuberculosis
Special Issues, Collections and Topics in MDPI journals
Dr. Semih Esin

E-Mail Website
Co-Guest Editor
Department of Translational Research on New Technologies in Medicine and Surgery, Università di Pisa, Pisa, Italy
Interests: immune system; mycobacterial infections; virulence factors and Mycobacterium tuberculosis; natural molecules with antimicrobial and /or immunomodulatory activity; infections sustained by microbial biofilms and the host's immune response
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Antibiotic resistance is one of the greatest global public health concerns that urgently needs to be resolved. Such a problem has stimulated much research activity aimed at identifying new non-traditional approaches to prevent/treat drug-resistant infections. One of the strategies under evaluation is inhibiting the production or activity of microbial virulence factors, such as adhesins, quorum sensing molecules, and toxins, to prevent bacterial adhesion to host cells and biofilm formation, inhibit bacterial communication, and downregulate the secretion systems.

In contrast to antibiotics, anti-virulence drugs do not directly inhibit bacterial growth, and this is expected to reduce selective pressures exerted on pathogen populations, avoiding the dissemination of antibiotic resistance. However, numerous challenges need to be solved before translating anti-virulence strategies into new treatments for patients.

In this context, the submission of contributions in the form of original research papers, short communications, or reviews to this Special Issue is encouraged. This issue aims to broaden knowledge about the mechanisms of action and efficacy of new antivirulence strategies against human bacterial and fungal pathogens and to better understand the therapeutic potential of this alternative antimicrobial approach.

Dr. Giuseppantonio Maisetta
Guest Editor
Prof. Giovanna Batoni
Dr. Semih Esin
Co-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. Microorganisms is an international peer-reviewed open access monthly 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

  • bacteria
  • fungi
  • pathogens
  • quorum-sensing
  • toxins
  • virulence
  • biofilm
  • secretion system

Published Papers (5 papers)

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Research

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15 pages, 1568 KiB  
Article
Quorum Quenching Strains Isolated from the Microbiota of Sea Anemones and Holothurians Attenuate Vibriocorallilyticus Virulence Factors and Reduce Mortality in Artemiasalina
by José Carlos Reina, Pedro Pérez and Inmaculada Llamas
Microorganisms 2022, 10(3), 631; https://doi.org/10.3390/microorganisms10030631 - 16 Mar 2022
Cited by 7 | Viewed by 2511
Abstract
Interference with quorum-sensing (QS) intercellular communication systems by the enzymatic disruption of N-acylhomoserine lactones (AHLs) in Gram-negative bacteria has become a promising strategy to fight bacterial infections. In this study, seven strains previously isolated from marine invertebrates and selected for their ability [...] Read more.
Interference with quorum-sensing (QS) intercellular communication systems by the enzymatic disruption of N-acylhomoserine lactones (AHLs) in Gram-negative bacteria has become a promising strategy to fight bacterial infections. In this study, seven strains previously isolated from marine invertebrates and selected for their ability to degrade C6 and C10-HSL, were identified as Acinetobacter junii, Ruegeria atlantica, Microbulbifer echini, Reinheimera aquimaris, and Pseudomonas sihuiensis. AHL-degrading activity against a wide range of synthetic AHLs were identified by using an agar well diffusion assay and Agrobacterium tumefaciens NTL4 and Chromobacterium violaceum CV026 and VIR07 as biosensors. High-performance liquid chromatography-mass spectrometry (HPLC-MS) analysis indicated that this activity was not due to an AHL lactonase. All the strains degraded Vibrio coralliilyticus AHLs in coculture experiments, while some strains reduced or abolished the production of virulence factors. In vivo assays showed that strains M3-111 and M3-127 reduced this pathogen’s virulence and increased the survival rate of Artemia salina up to 3-fold, indicating its potential use for biotechnological purposes. To our knowledge, this is the first study to describe AHL-degrading activities in some of these marine species. These findings highlight that the microbiota associated with marine invertebrates constitute an important underexplored source of biological valuable compounds. Full article
(This article belongs to the Special Issue Anti-virulence Strategies against Microbial Pathogens)
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17 pages, 3586 KiB  
Article
A Structural Approach to Anti-Virulence: A Discovery Pipeline
by Michael McCarthy, Monica Goncalves, Hannah Powell, Blake Morey, Madison Turner and Allan Rod Merrill
Microorganisms 2021, 9(12), 2514; https://doi.org/10.3390/microorganisms9122514 - 04 Dec 2021
Cited by 2 | Viewed by 3208
Abstract
The anti-virulence strategy is designed to prevent bacterial virulence factors produced by pathogenic bacteria from initiating and sustaining an infection. One family of bacterial virulence factors is the mono-ADP-ribosyltransferase toxins, which are produced by pathogens as tools to compromise the target host cell. [...] Read more.
The anti-virulence strategy is designed to prevent bacterial virulence factors produced by pathogenic bacteria from initiating and sustaining an infection. One family of bacterial virulence factors is the mono-ADP-ribosyltransferase toxins, which are produced by pathogens as tools to compromise the target host cell. These toxins are bacterial enzymes that exploit host cellular NAD+ as the donor substrate to modify an essential macromolecule acceptor target in the host cell. This biochemical reaction modifies the target macromolecule (often protein or DNA) and functions in a binary fashion to turn the target activity on or off by blocking or impairing a critical process or pathway in the host. A structural biology approach to the anti-virulence method to neutralize the cytotoxic effect of these factors requires the search and design of small molecules that bind tightly to the enzyme active site and prevent catalytic function essentially disarming the pathogen. This method requires a high-resolution structure to serve as the model for small molecule inhibitor development, which illuminates the path to drug development. This alternative strategy to antibiotic therapy represents a paradigm shift that may circumvent multi-drug resistance in the offending microbe through anti-virulence therapy. In this report, the rationale for the anti-virulence structural approach will be discussed along with recent efforts to apply this method to treat honey bee diseases using natural products. Full article
(This article belongs to the Special Issue Anti-virulence Strategies against Microbial Pathogens)
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14 pages, 13040 KiB  
Article
Xylitol Inhibits Growth and Blocks Virulence in Serratia marcescens
by Ahdab N. Khayyat, Wael A. H. Hegazy, Moataz A. Shaldam, Rasha Mosbah, Ahmad J. Almalki, Tarek S. Ibrahim, Maan T. Khayat, El-Sayed Khafagy, Wafaa E. Soliman and Hisham A. Abbas
Microorganisms 2021, 9(5), 1083; https://doi.org/10.3390/microorganisms9051083 - 18 May 2021
Cited by 38 | Viewed by 4550
Abstract
Serratia marcescens is an opportunistic nosocomial pathogen and causes wound and burn infections. It shows high resistance to antibiotics and its pathogenicity is mediated by an arsenal of virulence factors. Another therapeutic option to such infections is targeting quorum sensing (QS), which controls [...] Read more.
Serratia marcescens is an opportunistic nosocomial pathogen and causes wound and burn infections. It shows high resistance to antibiotics and its pathogenicity is mediated by an arsenal of virulence factors. Another therapeutic option to such infections is targeting quorum sensing (QS), which controls the expression of different S. marcescens virulence factors. Prevention of QS can deprive S. marcescens from its bacterial virulence without applying stress on the bacterial growth and facilitates the eradication of the bacteria by immunity. The objective of the current study is to explore the antimicrobial and antivirulence activities of xylitol against S. marcescens. Xylitol could inhibit the growth of S. marcescens. Sub-inhibitory concentrations of xylitol could inhibit biofilm formation, reduce prodigiosin production, and completely block protease activity. Moreover, xylitol decreased swimming motility, swarming motility and increased the sensitivity to hydrogen peroxide. The expression of rsmA, pigP, flhC, flhD fimA, fimC, shlA bsmB, and rssB genes that regulate virulence factor production was significantly downregulated by xylitol. In silico study showed that xylitol could bind with the SmaR receptor by hydrophobic interaction and hydrogen bonding, and interfere with the binding of the natural ligand with SmaR receptor. An in vivo mice survival test confirmed the ability of xylitol to protect mice against the virulence of S. marcescens. In conclusion, xylitol is a growth and virulence inhibitor in S. marcescens and can be employed for the treatment of S. marcescens wound and burn infections. Full article
(This article belongs to the Special Issue Anti-virulence Strategies against Microbial Pathogens)
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18 pages, 3698 KiB  
Article
Antivirulence Properties of a Low-Molecular-Weight Quaternized Chitosan Derivative against Pseudomonas aeruginosa
by Giuseppantonio Maisetta, Anna Maria Piras, Vincenzo Motta, Simona Braccini, Diletta Mazzantini, Federica Chiellini, Ylenia Zambito, Semih Esin and Giovanna Batoni
Microorganisms 2021, 9(5), 912; https://doi.org/10.3390/microorganisms9050912 - 24 Apr 2021
Cited by 9 | Viewed by 2094
Abstract
The co-occurrence of increasing rates of resistance to current antibiotics and the paucity of novel antibiotics pose major challenges for the treatment of bacterial infections. In this scenario, treatments targeting bacterial virulence have gained considerable interest as they are expected to exert a [...] Read more.
The co-occurrence of increasing rates of resistance to current antibiotics and the paucity of novel antibiotics pose major challenges for the treatment of bacterial infections. In this scenario, treatments targeting bacterial virulence have gained considerable interest as they are expected to exert a weaker selection for resistance than conventional antibiotics. In a previous study, we demonstrated that a low-molecular-weight quaternized chitosan derivative, named QAL, displays antibiofilm activity against the major pathogen Pseudomonas aeruginosa at subinhibitory concentrations. The aim of this study was to investigate whether QAL was able to inhibit the production of relevant virulence factors of P. aeruginosa. When tested in vitro at subinhibiting concentrations (0.31–0.62 mg/mL), QAL markedly reduced the production of pyocyanin, pyoverdin, proteases, and LasA, as well as inhibited the swarming motility of three out of four P. aeruginosa strains tested. Furthermore, quantitative reverse transcription PCR (qRT-PCR) analyses demonstrated that expression of lasI and rhlI, two QS-related genes, was highly downregulated in a representative P. aeruginosa strain. Confocal scanning laser microscopy analysis suggested that FITC-labelled QAL accumulates intracellularly following incubation with P. aeruginosa. In contrast, the reduced production of virulence factors was not evidenced when QAL was used as the main polymeric component of polyelectrolyte-based nanoparticles. Additionally, combination of sub-MIC concentrations of QAL and tobramycin significantly reduced biofilm formation of P. aeruginosa, likely due to a synergistic activity towards planktonic bacteria. Overall, the results obtained demonstrated an antivirulence activity of QAL, possibly due to polymer intracellular localization and QS-inhibition, and its ability to inhibit P. aeruginosa growth synergizing with tobramycin. Full article
(This article belongs to the Special Issue Anti-virulence Strategies against Microbial Pathogens)
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Review

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32 pages, 3839 KiB  
Review
The Case against Antibiotics and for Anti-Virulence Therapeutics
by Julia A. Hotinger, Seth T. Morris and Aaron E. May
Microorganisms 2021, 9(10), 2049; https://doi.org/10.3390/microorganisms9102049 - 28 Sep 2021
Cited by 24 | Viewed by 4397
Abstract
Although antibiotics have been indispensable in the advancement of modern medicine, there are downsides to their use. Growing resistance to broad-spectrum antibiotics is leading to an epidemic of infections untreatable by first-line therapies. Resistance is exacerbated by antibiotics used as growth factors in [...] Read more.
Although antibiotics have been indispensable in the advancement of modern medicine, there are downsides to their use. Growing resistance to broad-spectrum antibiotics is leading to an epidemic of infections untreatable by first-line therapies. Resistance is exacerbated by antibiotics used as growth factors in livestock, over-prescribing by doctors, and poor treatment adherence by patients. This generates populations of resistant bacteria that can then spread resistance genes horizontally to other bacterial species, including commensals. Furthermore, even when antibiotics are used appropriately, they harm commensal bacteria leading to increased secondary infection risk. Effective antibiotic treatment can induce bacterial survival tactics, such as toxin release and increasing resistance gene transfer. These problems highlight the need for new approaches to treating bacterial infection. Current solutions include combination therapies, narrow-spectrum therapeutics, and antibiotic stewardship programs. These mediate the issues but do not address their root cause. One emerging solution to these problems is anti-virulence treatment: preventing bacterial pathogenesis instead of using bactericidal agents. In this review, we discuss select examples of potential anti-virulence targets and strategies that could be developed into bacterial infection treatments: the bacterial type III secretion system, quorum sensing, and liposomes. Full article
(This article belongs to the Special Issue Anti-virulence Strategies against Microbial Pathogens)
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