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Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies 2.0

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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 (30 January 2023) | Viewed by 39668

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Dr. Francesca Micoli

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Guest Editor

GSK Vaccines Institute for Global Health (GVGH), 53100 Siena, Italy
Interests: infectious diseases; bacterial vaccines; glycoconjugate; carbohydrate; bio-assays; outer membrane vesicles; analytical methods
Special Issues, Collections and Topics in MDPI journals

Dr. Aleksandra Królicka

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Co-Guest Editor

Intercollegiate Faculty of Biotechnology UG-MUG, Laboratory of Biologically Active Compounds, University of Gdansk, 80-307 Gdansk, Poland
Interests: plant cell tissue; synergistic combination of drugs; biologically active compounds; transformation; phytopharmaceuticals; green synthesis of nanoparticles; drug resistance of bacteria
Special Issues, Collections and Topics in MDPI journals

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
Aleksandra Królicka
co-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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Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies in International Journal of Molecular Sciences (10 articles)

Published Papers (11 papers)

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Research

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11 pages, 2088 KiB

Open AccessArticle

Alanine-Dependent TCA Cycle Promotion Restores the Zhongshengmycin-Susceptibility in Xanthomonas oryzae

by Zhenyu Zou, Meiyun Lin, Peihua Shen and Yi Guan

Int. J. Mol. Sci. 2023, 24(3), 3004; https://doi.org/10.3390/ijms24033004 - 3 Feb 2023

Cited by 5 | Viewed by 1799

Abstract

Xanthomonas oryzae pv. oryzicola (Xoo) is a plant pathogenic bacterium that can cause rice bacterial blight disease, which results in a severe reduction in rice production. Antimicrobial-dependent microbial controlling is a useful way to control the spread and outbreak of plant pathogenic bacteria. However, the abuse and long-term use of antimicrobials also cause microbial antimicrobial resistance. As far as known, the mechanism of antimicrobial resistance in agricultural plant pathogenic bacteria still lacks prospecting. In this study, we explore the mechanism of Zhongshengmycin (ZSM)-resistance in Xoo by GC-MS-based metabolomic analysis. The results showed that the down-regulation of the TCA cycle was characteristic of antimicrobial resistance in Xoo, which was further demonstrated by the reduction of activity and gene expression levels of key enzymes in the TCA cycle. Furthermore, alanine was proven to reverse the ZSM resistance in Xoo by accelerating the TCA cycle in vivo. Our results are essential for understanding the mechanisms of ZSM resistance in Xoo and may provide new strategies for controlling this agricultural plant pathogen at the metabolic level. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies 2.0)

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14 pages, 1116 KiB

Open AccessArticle

Yeast Mannan-Rich Fraction Modulates Endogenous Reactive Oxygen Species Generation and Antibiotic Sensitivity in Resistant E. coli

by Helen Smith, Sharon Grant, Paula Meleady, Michael Henry, Donal O’Gorman, Martin Clynes and Richard Murphy

Int. J. Mol. Sci. 2023, 24(1), 218; https://doi.org/10.3390/ijms24010218 - 22 Dec 2022

Cited by 2 | Viewed by 2037

Abstract

Mannan-rich fraction (MRF) isolated from Saccharomyces cerevisiae has been studied for its beneficial impact on animal intestinal health. Herein, we examined how MRF affected the formation of reactive oxygen species (ROS), impacting antibiotic susceptibility in resistant Escherichia coli through the modulation of bacterial metabolism. The role of MRF in effecting proteomic change was examined using a proteomics-based approach. The results showed that MRF, when combined with bactericidal antibiotic treatment, increased ROS production in resistant E. coli by 59.29 ± 4.03% compared to the control (p ≤ 0.05). We further examined the effect of MRF alone and in combination with antibiotic treatment on E. coli growth and explored how MRF potentiates bacterial susceptibility to antibiotics via proteomic changes in key metabolic pathways. Herein we demonstrated that MRF supplementation in the growth media of ampicillin-resistant E. coli had a significant impact on the normal translational control of the central metabolic pathways, including those involved in the glycolysis–TCA cycle (p ≤ 0.05). Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies 2.0)

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10 pages, 573 KiB

Open AccessArticle

Staphylococcus aureus Keratitis in Taiwan: Genotyping, Antibiotic Susceptibility, and Clinical Features

by Ching-Hsi Hsiao, Eugene Yu-Chuan Kang, Lung-Kun Yeh, David H. K. Ma, Hung-Chi Chen, Kuo-Hsuan Hung and Yhu-Chering Huang

Int. J. Mol. Sci. 2022, 23(19), 11703; https://doi.org/10.3390/ijms231911703 - 3 Oct 2022

Cited by 3 | Viewed by 1960

Abstract

Staphylococcus aureus is an important pathogen for keratitis, a vision-threatening disease. We aimed to investigate the genotyping, antibiotic susceptibility, and clinical features of S. aureus keratitis, and to explore the possible role of Panton–Valentine leucocidin (PVL), a major virulence factor of S. aureus. We recruited 49 patients with culture-proven S. aureus keratitis between 2013 and 2017 at Chang Gung Memorial Hospital, Taiwan. PVL gene, multilocus sequence type (MLST), staphylococcal cassette chromosome mec (SCCmec), and pulsed-field gel electrophoresis (PFGE) were performed. Antibiotic susceptibility was verified using disk diffusion/E test. There were 49 patients with S. aureus keratitis; 17 (34.7%) were caused by methicillin-resistant S. aureus (MRSA) and 9 (18.4%) isolates had PVL genes. The predominant genotyping of MRSA isolates was CC59/PFGE type D/SCCmec V_T/PVL (+). All methicillin-sensitive S. aureus (MSSA) and approximately 60% MRSA were susceptible to fluoroquinolones. No significant differences in clinical features, treatments, and visual outcomes were observed between MRSA/MSSA or PVL(+)/PVL(−) groups. In Taiwan, approximately one third of S. aureus keratitis was caused by MRSA, mainly community-associated MRSA. Although MRSA isolates were more resistant than MSSA, clinical characteristics were similar between two groups. Fluoroquinolones could be good empiric antibiotics for S. aureus keratitis. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies 2.0)

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17 pages, 2896 KiB

Open AccessArticle

Response of Mycobacterium smegmatis to the Cytochrome bcc Inhibitor Q203

by Priyanka Chauhan, Santhe Amber van der Meulen, João Miguel Simões Caetano, Hojjat Ghasemi Goojani, Dennis Botman, Rob van Spanning, Holger Lill and Dirk Bald

Int. J. Mol. Sci. 2022, 23(18), 10331; https://doi.org/10.3390/ijms231810331 - 7 Sep 2022

Cited by 4 | Viewed by 2384

Abstract

For the design of next-generation tuberculosis chemotherapy, insight into bacterial defence against drugs is required. Currently, targeting respiration has attracted strong attention for combatting drug-resistant mycobacteria. Q203 (telacebec), an inhibitor of the cytochrome bcc complex in the mycobacterial respiratory chain, is currently evaluated in phase-2 clinical trials. Q203 has bacteriostatic activity against M. tuberculosis, which can be converted to bactericidal activity by concurrently inhibiting an alternative branch of the mycobacterial respiratory chain, cytochrome bd. In contrast, non-tuberculous mycobacteria, such as Mycobacterium smegmatis, show only very little sensitivity to Q203. In this report, we investigated factors that M. smegmatis employs to adapt to Q203 in the presence or absence of a functional cytochrome bd, especially regarding its terminal oxidases. In the presence of a functional cytochrome bd, M. smegmatis responds to Q203 by increasing the expression of cytochrome bcc as well as of cytochrome bd, whereas a M. smegmatisbd-KO strain adapted to Q203 by increasing the expression of cytochrome bcc. Interestingly, single-cell studies revealed cell-to-cell variability in drug adaptation. We also investigated the role of a putative second cytochrome bd isoform postulated for M. smegmatis. Although this putative isoform showed differential expression in response to Q203 in the M. smegmatisbd-KO strain, it did not display functional features similar to the characterised cytochrome bd variant. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies 2.0)

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20 pages, 3006 KiB

Open AccessArticle

Liposomal Delivery of Newly Identified Prophage Lysins in a Pseudomonas aeruginosa Model

by Diana Morais, Luís Tanoeiro, Andreia T. Marques, Tiago Gonçalves, Aida Duarte, António Pedro Alves Matos, Joana S. Vital, Maria Eugénia Meirinhos Cruz, Manuela Colla Carvalheiro, Elsa Anes, Jorge M. B. Vítor, Maria Manuela Gaspar and Filipa F. Vale

Int. J. Mol. Sci. 2022, 23(17), 10143; https://doi.org/10.3390/ijms231710143 - 4 Sep 2022

Cited by 5 | Viewed by 3173

Abstract

Pseudomonas aeruginosa is a Gram-negative opportunistic bacterium that presents resistance to several antibiotics, thus, representing a major threat to human and animal health. Phage-derived products, namely lysins, or peptidoglycan-hydrolyzing enzymes, can be an effective weapon against antibiotic-resistant bacteria. Whereas in Gram-positive bacteria, lysis from without is facilitated by the exposed peptidoglycan layer, this is not possible in the outer membrane-protected peptidoglycan of Gram-negative bacteria. Here, we suggest the encapsulation of lysins in liposomes as a delivery system against Gram-negative bacteria, using the model of P. aeruginosa. Bioinformatic analysis allowed for the identification of 38 distinct complete prophages within 66 P. aeruginosa genomes (16 of which newly sequenced) and led to the identification of 19 lysins of diverse sequence and function, 5 of which proceeded to wet lab analysis. The four purifiable lysins showed hydrolytic activity against Gram-positive bacterial lawns and, on zymogram assays, constituted of autoclaved P. aeruginosa cells. Additionally, lysins Pa7 and Pa119 combined with an outer membrane permeabilizer showed activity against P. aeruginosa cells. These two lysins were successfully encapsulated in DMPC:DOPE:CHEMS (molar ratio 4:4:2) liposomes with an average encapsulation efficiency of 33.33% and 32.30%, respectively. The application of the encapsulated lysins to the model P. aeruginosa led to a reduction in cell viability and resulted in cell lysis as observed in MTT cell viability assays and electron microscopy. In sum, we report here that prophages may be important sources of new enzybiotics, with prophage lysins showing high diversity and activity. In addition, these enzybiotics following their incorporation in liposomes were able to potentiate their antibacterial effect against the Gram-negative bacteria P. aeruginosa, used as the model. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies 2.0)

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16 pages, 1911 KiB

Open AccessArticle

Synergistic Antibacterial Activity with Conventional Antibiotics and Mechanism of Action of Shikonin against Methicillin-Resistant Staphylococcus aureus

by Qian-Qian Li, Hee-Sung Chae, Ok-Hwa Kang and Dong-Yeul Kwon

Int. J. Mol. Sci. 2022, 23(14), 7551; https://doi.org/10.3390/ijms23147551 - 7 Jul 2022

Cited by 15 | Viewed by 2429

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a troublesome pathogen that poses a global threat to public health. Shikonin (SKN) isolated from Lithospermum erythrorhizon (L. erythrorhizon) possesses a variety of biological activities. This study aims to explore the effect of the combined application of SKN and traditional antibiotics on the vitality of MRSA and the inherent antibacterial mechanism of SKN. The synergies between SKN and antibiotics against MRSA and its clinical strain have been demonstrated by the checkerboard assay and the time-kill assay. The effect of SKN on disrupting the integrity and permeability of bacterial cell membranes was verified by a nucleotide and protein leakage assay and a bacteriolysis assay. As determined by crystal violet staining, SKN inhibited the biofilm formation of clinical MRSA strains. The results of Western blot and qRT-PCR showed that SKN could inhibit the expression of proteins and genes related to drug resistance and S. aureus exotoxins. SKN inhibited the ability of RAW264.7 cells to release the pro-inflammatory cytokines TNF-α and IL-6, as measured by ELISA. Our findings suggest that SKN has the potential to be developed as a promising alternative for the treatment of MRSA infections. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies 2.0)

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14 pages, 4938 KiB

Open AccessArticle

Identification of Bacterial Membrane Selectivity of Romo1-Derived Antimicrobial Peptide AMPR-22 via Molecular Dynamics

by Hana Kim, Young Do Yoo and Gi Young Lee

Int. J. Mol. Sci. 2022, 23(13), 7404; https://doi.org/10.3390/ijms23137404 - 3 Jul 2022

Cited by 4 | Viewed by 2371

Abstract

The abuse or misuse of antibiotics has caused the emergence of extensively drug-resistant (XDR) bacteria, rendering most antibiotics ineffective and increasing the mortality rate of patients with bacteremia or sepsis. Antimicrobial peptides (AMPs) are proposed to overcome this problem; however, many AMPs have attenuated antimicrobial activities with hemolytic toxicity in blood. Recently, AMPR-11 and its optimized derivative, AMPR-22, were reported to be potential candidates for the treatment of sepsis with a broad spectrum of antimicrobial activity and low hemolytic toxicity. Here, we performed molecular dynamics (MD) simulations to clarify the mechanism of lower hemolytic toxicity and higher efficacy of AMPR-22 at an atomic level. We found four polar residues in AMPR-11 bound to a model mimicking the bacterial inner/outer membranes preferentially over eukaryotic plasma membrane. AMPR-22 whose polar residues were replaced by lysine showed a 2-fold enhanced binding affinity to the bacterial membrane by interacting with bacterial specific lipids (lipid A or cardiolipin) via hydrogen bonds. The MD simulations were confirmed experimentally in models that partially mimic bacteremia conditions in vitro and ex vivo. The present study demonstrates why AMPR-22 showed low hemolytic toxicity and this approach using an MD simulation would be helpful in the development of AMPs. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies 2.0)

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Review

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24 pages, 2904 KiB

Open AccessReview

Toward a Shigella Vaccine: Opportunities and Challenges to Fight an Antimicrobial-Resistant Pathogen

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

Int. J. Mol. Sci. 2023, 24(5), 4649; https://doi.org/10.3390/ijms24054649 - 28 Feb 2023

Cited by 9 | Viewed by 5983

Abstract

Shigellosis causes more than 200,000 deaths worldwide and most of this burden falls on Low- and Middle-Income Countries (LMICs), with a particular incidence in children under 5 years of age. In the last decades, Shigella has become even more worrisome because of the onset of antimicrobial-resistant strains (AMR). Indeed, the WHO has listed Shigella as one of the priority pathogens for the development of new interventions. To date, there are no broadly available vaccines against shigellosis, but several candidates are being evaluated in preclinical and clinical studies, bringing to light very important data and information. With the aim to facilitate the understanding of the state-of-the-art of Shigella vaccine development, here we report what is known about Shigella epidemiology and pathogenesis with a focus on virulence factors and potential antigens for vaccine development. We discuss immunity after natural infection and immunization. In addition, we highlight the main characteristics of the different technologies that have been applied for the development of a vaccine with broad protection against Shigella. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies 2.0)

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26 pages, 1355 KiB

Open AccessReview

Polysaccharides’ Structures and Functions in Biofilm Architecture of Antimicrobial-Resistant (AMR) Pathogens

by Evita Balducci, Francesco Papi, Daniela Eloisa Capialbi and Linda Del Bino

Int. J. Mol. Sci. 2023, 24(4), 4030; https://doi.org/10.3390/ijms24044030 - 17 Feb 2023

Cited by 32 | Viewed by 4830

Abstract

Bacteria and fungi have developed resistance to the existing therapies such as antibiotics and antifungal drugs, and multiple mechanisms are mediating this resistance. Among these, the formation of an extracellular matrix embedding different bacterial cells, called biofilm, is an effective strategy through which bacterial and fungal cells are establishing a relationship in a unique environment. The biofilm provides them the possibility to transfer genes conferring resistance, to prevent them from desiccation and to impede the penetration of antibiotics or antifungal drugs. Biofilms are formed of several constituents including extracellular DNA, proteins and polysaccharides. Depending on the bacteria, different polysaccharides form the biofilm matrix in different microorganisms, some of them involved in the first stage of cells’ attachment to surfaces and to each other, and some responsible for giving the biofilm structure resistance and stability. In this review, we describe the structure and the role of different polysaccharides in bacterial and fungal biofilms, we revise the analytical methods to characterize them quantitatively and qualitatively and finally we provide an overview of potential new antimicrobial therapies able to inhibit biofilm formation by targeting exopolysaccharides. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies 2.0)

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52 pages, 1778 KiB

Open AccessReview

Insights into Carbapenem Resistance in Vibrio Species: Current Status and Future Perspectives

by Joanna Xuan Hui Goh, Loh Teng-Hern Tan, Jodi Woan-Fei Law, Kooi-Yeong Khaw, Nurul-Syakima Ab Mutalib, Ya-Wen He, Bey-Hing Goh, Kok-Gan Chan, Learn-Han Lee and Vengadesh Letchumanan

Int. J. Mol. Sci. 2022, 23(20), 12486; https://doi.org/10.3390/ijms232012486 - 18 Oct 2022

Cited by 11 | Viewed by 3234

Abstract

The increasing prevalence of resistance in carbapenems is an escalating concern as carbapenems are reserved as last-line antibiotics. Although indiscriminate antibiotic usage is considered the primary cause for resistance development, increasing evidence revealed that inconsequential strains without any direct clinical relevance to carbapenem usage are harboring carbapenemase genes. This phenomenon indirectly implies that environmental microbial populations could be the ‘hidden vectors’ propelling carbapenem resistance. This work aims to explore the carbapenem-resistance profile of Vibrio species across diverse settings. This review then proceeds to identify the different factors contributing to the dissemination of the resistance traits and defines the transmission pathways of carbapenem resistance. Deciphering the mechanisms for carbapenem resistance acquisition could help design better prevention strategies to curb the progression of antimicrobial resistance development. To better understand this vast reservoir selecting for carbapenem resistance in non-clinical settings, Vibrio species is also prospected as one of the potential indicator strains for carbapenem resistance in the environment. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies 2.0)

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25 pages, 3120 KiB

Open AccessReview

How Do Transposable Elements Activate Expression of Transcriptionally Silent Antibiotic Resistance Genes?

by Aleksander Lipszyc, Magdalena Szuplewska and Dariusz Bartosik

Int. J. Mol. Sci. 2022, 23(15), 8063; https://doi.org/10.3390/ijms23158063 - 22 Jul 2022

Cited by 18 | Viewed by 8128

Abstract

The rapidly emerging phenomenon of antibiotic resistance threatens to substantially reduce the efficacy of available antibacterial therapies. Dissemination of resistance, even between phylogenetically distant bacterial species, is mediated mainly by mobile genetic elements, considered to be natural vectors of horizontal gene transfer. Transposable elements (TEs) play a major role in this process—due to their highly recombinogenic nature they can mobilize adjacent genes and can introduce them into the pool of mobile DNA. Studies investigating this phenomenon usually focus on the genetic load of transposons and the molecular basis of their mobility. However, genes introduced into evolutionarily distant hosts are not necessarily expressed. As a result, bacterial genomes contain a reservoir of transcriptionally silent genetic information that can be activated by various transposon-related recombination events. The TEs themselves along with processes associated with their transposition can introduce promoters into random genomic locations. Thus, similarly to integrons, they have the potential to convert dormant genes into fully functional antibiotic resistance determinants. In this review, we describe the genetic basis of such events and by extension the mechanisms promoting the emergence of new drug-resistant bacterial strains. Full article

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies 2.0)

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