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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 (31 May 2021) | Viewed by 50875

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Dr. Francesca Micoli

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GSK Vaccines Institute for Global Health (GVGH), 53100 Siena, Italy
Interests: infectious diseases; bacterial vaccines; glycoconjugate; carbohydrate; bio-assays; outer membrane vesicles; analytical methods
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Special Issue Information

Dear Colleagues,

The use of antibiotics has transformed the treatment of bacterial infections, saving and improving the health of many patients worldwide. However, the global emergence and spread of antimicrobial resistance (AMR) has been highlighted as one of the major global health challenges by different health organizations, compromising the ability to prevent and cure a wide range of infectious diseases. An integrated strategy that includes different interventions is required to fight AMR effectively. This includes the development of new molecules and the search for alternative microbe targets, molecular knowledge about mechanisms of resistance, faster diagnostic tests, monoclonal antibodies, microbiome interventions, use of bacteriophages, and new approaches to deliver small-molecule antibacterials into bacteria. Vaccines can also play a major role. Vaccination has the benefit of sustainability, can be used for decades without generating significant resistance, and can slow the spread of antibiotic resistance both directly and indirectly.

Dr. Francesca Micoli
Guest Editor

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Keywords

Antimicrobial resistance
Mechanisms of antimicrobial resistance
Rapid antimicrobial susceptible assays
Drug discovery
Antibiotics
Vaccine
Monoclonal antibodies
Infectious diseases

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Related Special Issue

Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies 2.0 in International Journal of Molecular Sciences (11 articles)

Published Papers (10 papers)

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Research

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25 pages, 3669 KiB

Open AccessArticle

Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies

by Sandra Salillas, Juan José Galano-Frutos, Alejandro Mahía, Ritwik Maity, María Conde-Giménez, Ernesto Anoz-Carbonell, Helena Berlamont, Adrian Velazquez-Campoy, Eliette Touati, Uwe Mamat, Ulrich E. Schaible, José A. Gálvez, María D. Díaz-de-Villegas, Freddy Haesebrouck, José A. Aínsa and Javier Sancho

Int. J. Mol. Sci. 2021, 22(18), 10137; https://doi.org/10.3390/ijms221810137 - 20 Sep 2021

Cited by 5 | Viewed by 3324

Abstract

Antimicrobial resistant (AMR) bacteria constitute a global health concern. Helicobacter pylori is a Gram-negative bacterium that infects about half of the human population and is a major cause of peptic ulcer disease and gastric cancer. Increasing resistance to triple and quadruple H. pylori eradication therapies poses great challenges and urges the development of novel, ideally narrow spectrum, antimicrobials targeting H. pylori. Here, we describe the antimicrobial spectrum of a family of nitrobenzoxadiazol-based antimicrobials initially discovered as inhibitors of flavodoxin: an essential H. pylori protein. Two groups of inhibitors are described. One group is formed by narrow-spectrum compounds, highly specific for H. pylori, but ineffective against enterohepatic Helicobacter species and other Gram-negative or Gram-positive bacteria. The second group includes extended-spectrum antimicrobials additionally targeting Gram-positive bacteria, the Gram-negative Campylobacter jejuni, and most Helicobacter species, but not affecting other Gram-negative pathogens. To identify the binding site of the inhibitors in the flavodoxin structure, several H. pylori-flavodoxin variants have been engineered and tested using isothermal titration calorimetry. An initial study of the inhibitors capacity to generate resistances and of their synergism with antimicrobials commonly used in H. pylori eradication therapies is described. The narrow-spectrum inhibitors, which are expected to affect the microbiota less dramatically than current antimicrobial drugs, offer an opportunity to develop new and specific H. pylori eradication combinations to deal with AMR in H. pylori. On the other hand, the extended-spectrum inhibitors constitute a new family of promising antimicrobials, with a potential use against AMR Gram-positive bacterial pathogens. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies)

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15 pages, 2195 KiB

Open AccessArticle

Engineering a Novel Bivalent Oral Vaccine against Enteric Fever

by Annelise Soulier, Claudia Prevosto, Mary Chol, Livija Deban and Rocky M. Cranenburgh

Int. J. Mol. Sci. 2021, 22(6), 3287; https://doi.org/10.3390/ijms22063287 - 23 Mar 2021

Cited by 4 | Viewed by 3984

Abstract

Enteric fever is a major global healthcare issue caused largely by Salmonella enterica serovars Typhi and Paratyphi A. The objective of this study was to develop a novel, bivalent oral vaccine capable of protecting against both serovars. Our approach centred on genetically engineering the attenuated S. Typhi ZH9 strain, which has an excellent safety record in clinical trials, to introduce two S. Paratyphi A immunogenic elements: flagellin H:a and lipopolysaccharide (LPS) O:2. We first replaced the native S. Typhi fliC gene encoding flagellin with the highly homologous fliC gene from S. Paratyphi A using Xer-cise technology. Next, we replaced the S. Typhi rfbE gene encoding tyvelose epimerase with a spacer sequence to enable the sustained expression of O:2 LPS and prevent its conversion to O:9 through tyvelose epimerase activity. The resulting new strain, ZH9PA, incorporated these two genetic changes and exhibited comparable growth kinetics to the parental ZH9 strain. A formulation containing both ZH9 and ZH9PA strains together constitutes a new bivalent vaccine candidate that targets both S. Typhi and S. Paratyphi A antigens to address a major global healthcare gap for enteric fever prophylaxis. This vaccine is now being tested in a Phase I clinical trial (NCT04349553). Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies)

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19 pages, 4361 KiB

Open AccessArticle

Myricetin as an Antivirulence Compound Interfering with a Morphological Transformation into Coccoid Forms and Potentiating Activity of Antibiotics against Helicobacter pylori

by Paweł Krzyżek, Paweł Migdał, Emil Paluch, Magdalena Karwańska, Alina Wieliczko and Grażyna Gościniak

Int. J. Mol. Sci. 2021, 22(5), 2695; https://doi.org/10.3390/ijms22052695 - 7 Mar 2021

Cited by 30 | Viewed by 3398

Abstract

Helicobacter pylori, a gastric pathogen associated with a broad range of stomach diseases, has a high tendency to become resistant to antibiotics. One of the most important factors related to therapeutic failures is its ability to change from a spiral to a coccoid form. Therefore, the main aim of our original article was to determine the influence of myricetin, a natural compound with an antivirulence action, on the morphological transformation of H. pylori and check the potential of myricetin to increase the activity of antibiotics against this pathogen. We observed that sub-minimal inhibitory concentrations (sub-MICs) of this compound have the ability to slow down the process of transformation into coccoid forms and reduce biofilm formation of this bacterium. Using checkerboard assays, we noticed that the exposure of H. pylori to sub-MICs of myricetin enabled a 4–16-fold reduction in MICs of all classically used antibiotics (amoxicillin, clarithromycin, tetracycline, metronidazole, and levofloxacin). Additionally, RT-qPCR studies of genes related to the H. pylori morphogenesis showed a decrease in their expression during exposure to myricetin. This inhibitory effect was more strongly seen for genes involved in the muropeptide monomers shortening (csd3, csd6, csd4, and amiA), suggesting their significant participation in the spiral-to-coccoid transition. To our knowledge, this is the first research showing the ability of any compound to synergistically interact with all five antibiotics against H. pylori and the first one showing the capacity of a natural substance to interfere with the morphological transition of H. pylori from spiral to coccoid forms. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies)

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26 pages, 6072 KiB

Open AccessArticle

Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria

by Aneta Kaczor, Karolina Witek, Sabina Podlewska, Veronique Sinou, Joanna Czekajewska, Ewa Żesławska, Agata Doroz-Płonka, Annamaria Lubelska, Gniewomir Latacz, Wojciech Nitek, Markus Bischoff, Sandrine Alibert, Jean-Marie Pagès, Claus Jacob, Elżbieta Karczewska, Jean-Michel Bolla and Jadwiga Handzlik

Int. J. Mol. Sci. 2021, 22(4), 2062; https://doi.org/10.3390/ijms22042062 - 19 Feb 2021

Cited by 7 | Viewed by 3914

Abstract

In the search for an effective strategy to overcome antimicrobial resistance, a series of new morpholine-containing 5-arylideneimidazolones differing within either the amine moiety or at position five of imidazolones was explored as potential antibiotic adjuvants against Gram-positive and Gram-negative bacteria. Compounds (7–23) were tested for oxacillin adjuvant properties in the Methicillin-susceptible S. aureus (MSSA) strain ATCC 25923 and Methicillin-resistant S. aureus MRSA 19449. Compounds 14–16 were tested additionally in combination with various antibiotics. Molecular modelling was performed to assess potential mechanism of action. Microdilution and real-time efflux (RTE) assays were carried out in strains of K. aerogenes to determine the potential of compounds 7–23 to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were determined experimentally. Two compounds (10, 15) containing non-condensed aromatic rings, significantly reduced oxacillin MICs in MRSA 19449, while 15 additionally enhanced the effectiveness of ampicillin. Results of molecular modelling confirmed the interaction with the allosteric site of PBP2a as a probable MDR-reversing mechanism. In RTE, the compounds inhibited AcrAB-TolC even to 90% (19). The 4-phenylbenzylidene derivative (15) demonstrated significant MDR-reversal “dual action” for β-lactam antibiotics in MRSA and inhibited AcrAB-TolC in K. aerogenes. 15 displayed also satisfied solubility and safety towards CYP3A4 in vitro. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies)

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20 pages, 3695 KiB

Open AccessArticle

Functional Identification of Serine Hydroxymethyltransferase as a Key Gene Involved in Lysostaphin Resistance and Virulence Potential of Staphylococcus aureus Strains

by Nayab Batool, Kwan Soo Ko, Akhilesh Kumar Chaurasia and Kyeong Kyu Kim

Int. J. Mol. Sci. 2020, 21(23), 9135; https://doi.org/10.3390/ijms21239135 - 30 Nov 2020

Cited by 13 | Viewed by 3439

Abstract

Gaining an insight into the mechanism underlying antimicrobial-resistance development in Staphylococcus aureus is crucial for identifying effective antimicrobials. We isolated S. aureus sequence type 72 from a patient in whom the S. aureus infection was highly resistant to various antibiotics and lysostaphin, but no known resistance mechanisms could explain the mechanism of lysostaphin resistance. Genome-sequencing followed by subtractive and functional genomics revealed that serine hydroxymethyltransferase (glyA or shmT gene) plays a key role in lysostaphin resistance. Serine hydroxymethyltransferase (SHMT) is indispensable for the one-carbon metabolism of serine/glycine interconversion and is linked to folate metabolism. Functional studies revealed the involvement of SHMT in lysostaphin resistance, as ΔshmT was susceptible to the lysostaphin, while complementation of the knockout expressing shmT restored resistance against lysostaphin. In addition, the ΔshmT showed reduced virulence under in vitro (mammalian cell lines infection) and in vivo (wax-worm infection) models. The SHMT inhibitor, serine hydroxymethyltransferase inhibitor 1 (SHIN1), protected the 50% of the wax-worm infected with wild type S. aureus. These results suggest SHMT is relevant to the extreme susceptibility to lysostaphin and the host immune system. Thus, the current study established that SHMT plays a key role in lysostaphin resistance development and in determining the virulence potential of multiple drug-resistant S. aureus. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies)

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10 pages, 1738 KiB

Open AccessArticle

The Mechanism of Bisdemethoxycurcumin Enhances Conventional Antibiotics against Methicillin-Resistant Staphylococcus aureus

by Shu Wang, Min-Chul Kim, Ok-Hwa Kang and Dong-Yeul Kwon

Int. J. Mol. Sci. 2020, 21(21), 7945; https://doi.org/10.3390/ijms21217945 - 26 Oct 2020

Cited by 13 | Viewed by 2594

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) infection has posed a serious threat to public health, therefore, the development of new antibacterial drugs is imperative. Bisdemethoxycurcumin (BDMC) is a curcumin analog that exists in nature and possesses extensive pharmacological actions. This review focuses on investigating the antibacterial activity of BDMC alone or in combination with three antibiotics against MRSA. We determined the minimal inhibitory concentration of BDMC, with a broth microdilution assay, and the value against all six strains was 7.8 μg/mL. The synergistic effect of BDMC combined with the antibiotics was determined using a checkerboard dilution test and a time–kill curve assay. The results showed that the antimicrobial effect of BDMC combined with antibiotics was superior to treatment with that of a single agent alone. We examined the antibacterial activity of BDMC in the presence of a membrane-permeabilizing agent and an ATPase-inhibiting agent, respectively. In addition, we analyzed the mecA transcription gene and the penicillin-binding protein 2a (PBP2a) level of MRSA treated with BDMC by quantitative RT-PCR or Western blot assay. The gene transcription and the protein level were significantly inhibited. This study demonstrated that BDMC has potent antibacterial activity, and proved that BDMC may be a potential natural modulator of antibiotics. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies)

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Review

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17 pages, 1658 KiB

Open AccessReview

Treat Me Well or Will Resist: Uptake of Mobile Genetic Elements Determine the Resistome of Corynebacterium striatum

by Benjamin Leyton, Juliana Nunes Ramos, Paulo Victor Pereira Baio, João Flávio Carneiro Veras, Cassius Souza, Andreas Burkovski, Ana Luíza Mattos-Guaraldi, Verônica Viana Vieira and Michel Abanto Marin

Int. J. Mol. Sci. 2021, 22(14), 7499; https://doi.org/10.3390/ijms22147499 - 13 Jul 2021

Cited by 22 | Viewed by 4103

Abstract

Corynebacterium striatum, a bacterium that is part of the normal skin microbiota, is also an opportunistic pathogen. In recent years, reports of infections and in-hospital and nosocomial outbreaks caused by antimicrobial multidrug-resistant C. striatum strains have been increasing worldwide. However, there are no studies about the genomic determinants related to antimicrobial resistance in C. striatum. This review updates global information related to antimicrobial resistance found in C. striatum and highlights the essential genomic aspects in its persistence and dissemination. The resistome of C. striatum comprises chromosomal and acquired elements. Resistance to fluoroquinolones and daptomycin are due to mutations in chromosomal genes. Conversely, resistance to macrolides, tetracyclines, phenicols, beta-lactams, and aminoglycosides are associated with mobile genomic elements such as plasmids and transposons. The presence and diversity of insertion sequences suggest an essential role in the expression of antimicrobial resistance genes (ARGs) in genomic rearrangements and their potential to transfer these elements to other pathogens. The present study underlines that the resistome of C. striatum is dynamic; it is in evident expansion and could be acting as a reservoir for ARGs. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies)

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18 pages, 1843 KiB

Open AccessReview

Strategies to Tackle Antimicrobial Resistance: The Example of Escherichia coli and Pseudomonas aeruginosa

by Giada Antonelli, Luigia Cappelli, Paolo Cinelli, Rossella Cuffaro, Benedetta Manca, Sonia Nicchi, Serena Tondi, Giacomo Vezzani, Viola Viviani, Isabel Delany, Maria Scarselli and Francesca Schiavetti

Int. J. Mol. Sci. 2021, 22(9), 4943; https://doi.org/10.3390/ijms22094943 - 6 May 2021

Cited by 17 | Viewed by 6309

Abstract

Traditional antimicrobial treatments consist of drugs which target different essential functions in pathogens. Nevertheless, bacteria continue to evolve new mechanisms to evade this drug-mediated killing with surprising speed on the deployment of each new drug and antibiotic worldwide, a phenomenon called antimicrobial resistance (AMR). Nowadays, AMR represents a critical health threat, for which new medical interventions are urgently needed. By 2050, it is estimated that the leading cause of death will be through untreatable AMR pathogens. Although antibiotics remain a first-line treatment, non-antibiotic therapies such as prophylactic vaccines and therapeutic monoclonal antibodies (mAbs) are increasingly interesting alternatives to limit the spread of such antibiotic resistant microorganisms. For the discovery of new vaccines and mAbs, the search for effective antigens that are able to raise protective immune responses is a challenging undertaking. In this context, outer membrane vesicles (OMV) represent a promising approach, as they recapitulate the complete antigen repertoire that occurs on the surface of Gram-negative bacteria. In this review, we present Escherichia coli and Pseudomonas aeruginosa as specific examples of key AMR threats caused by Gram-negative bacteria and we discuss the current status of mAbs and vaccine approaches under development as well as how knowledge on OMV could benefit antigen discovery strategies. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies)

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20 pages, 3373 KiB

Open AccessReview

Prophylaxis and Treatment against Klebsiella pneumoniae: Current Insights on This Emerging Anti-Microbial Resistant Global Threat

by Vanessa Arato, Maria Michelina Raso, Gianmarco Gasperini, Francesco Berlanda Scorza and Francesca Micoli

Int. J. Mol. Sci. 2021, 22(8), 4042; https://doi.org/10.3390/ijms22084042 - 14 Apr 2021

Cited by 41 | Viewed by 12285

Abstract

Klebsiella pneumoniae (Kp) is an opportunistic pathogen and the leading cause of healthcare-associated infections, mostly affecting subjects with compromised immune systems or suffering from concurrent bacterial infections. However, the dramatic increase in hypervirulent strains and the emergence of new multidrug-resistant clones resulted in Kp occurrence among previously healthy people and in increased morbidity and mortality, including neonatal sepsis and death across low- and middle-income countries. As a consequence, carbapenem-resistant and extended spectrum β-lactamase-producing Kp have been prioritized as a critical anti-microbial resistance threat by the World Health Organization and this has renewed the interest of the scientific community in developing a vaccine as well as treatments alternative to the now ineffective antibiotics. Capsule polysaccharide is the most important virulence factor of Kp and plays major roles in the pathogenesis but its high variability (more than 100 different types have been reported) makes the identification of a universal treatment or prevention strategy very challenging. However, less variable virulence factors such as the O-Antigen, outer membrane proteins as fimbriae and siderophores might also be key players in the fight against Kp infections. Here, we review elements of the current status of the epidemiology and the molecular pathogenesis of Kp and explore specific bacterial antigens as potential targets for both prophylactic and therapeutic solutions. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies)

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22 pages, 618 KiB

Open AccessReview

Passive Immunoprophylaxis against Respiratory Syncytial Virus in Children: Where Are We Now?

by Alessandro Rocca, Carlotta Biagi, Sara Scarpini, Arianna Dondi, Silvia Vandini, Luca Pierantoni and Marcello Lanari

Int. J. Mol. Sci. 2021, 22(7), 3703; https://doi.org/10.3390/ijms22073703 - 2 Apr 2021

Cited by 23 | Viewed by 5807

Abstract

Respiratory syncytial virus (RSV) represents the main cause of acute respiratory tract infections in children worldwide and is the leading cause of hospitalization in infants. RSV infection is a self-limiting condition and does not require antibiotics. However hospitalized infants with clinical bronchiolitis often receive antibiotics for fear of bacteria coinfection, especially when chest radiography is performed due to similar radiographic appearance of infiltrate and atelectasis. This may lead to unnecessary antibiotic prescription, additional cost, and increased risk of development of resistance. Despite the considerable burden of RSV bronchiolitis, to date, only symptomatic treatment is available, and there are no commercially available vaccines. The only licensed passive immunoprophylaxis is palivizumab. The high cost of this monoclonal antibody (mAb) has led to limiting its prescription only for high-risk children: infants with chronic lung disease, congenital heart disease, neuromuscular disorders, immunodeficiencies, and extreme preterm birth. Nevertheless, it has been shown that the majority of hospitalized RSV-infected children do not fully meet the criteria for immune prophylaxis. While waiting for an effective vaccine, passive immune prophylaxis in children is mandatory. There are a growing number of RSV passive immunization candidates under development intended for RSV prevention in all infants. In this review, we describe the state-of-the-art of palivizumab’s usage and summarize the clinical and preclinical trials regarding the development of mAbs with a better cost-effectiveness ratio. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies)

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