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The Quest for Novel Antimicrobials: From Chemical Synthesis and Discovery to Mechanisms of Action and Resistance

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A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Novel Antimicrobial Agents".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 33574

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Dr. Jorge H. Leitão

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Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
Interests: molecular microbiology; biology and biochemistry of Gram-negative bacteria; bacterial small non-coding regulatory RNAs; mechanisms of resistance to antimicrobials; development of new antimicrobials; vaccine research
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Dr. Luis G. Alves

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Centro de Química Estrutural, Associação do Instituto Superior Técnico para a Investigação e Desenvolvimento, Lisbon, Portugal
Interests: azamacrocyles; antimicrobials; antitumorals; metallodrugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The ongoing worldwide viral pandemic that is affecting all of us highlights the problem of microbial resistance to available drugs and the urgent need for the development of novel antibacterial, antifungal and antiviral compounds. The current rush for the development of antivirals and vaccines to control SARS-COV2 points out the need for the research of novel antifungal and antibacterial compounds to cope with established pathogens and emerging multiresistant strains. In recent years, research laboratories and academia have taken the front edge of research on antimicrobials, as the introduction of novel antibiotics into the market has continuously declined.

This Special Issue aims to gather papers describing novel antimicrobial molecules that are active against bacteria, fungi and viruses, originating from chemical synthesis, repositioning of existent drugs, or from natural sources, like plants, herbs and spices extracts. We are also welcoming papers describing the discovery of novel targets and mechanisms of action and resistance, as well as on the use of omics and bioinformatic approaches to advance the field of novel antimicrobials discovery.

Prof. Jorge H. Leitão
Dr. Luis G. Alves
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. Antibiotics 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 2900 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

antibacterial
antifungal
antiviral
new synthetic routes
drug discovery
mechanisms of action
antimicrobial resistance

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Published Papers (8 papers)

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Research

9 pages, 652 KiB

Open AccessArticle

Repurposing Avermectins and Milbemycins against Mycobacteroides abscessus and Other Nontuberculous Mycobacteria

by Lara Muñoz-Muñoz, Carolyn Shoen, Gaye Sweet, Asunción Vitoria, Tim J. Bull, Michael Cynamon, Charles J. Thompson and Santiago Ramón-García

Antibiotics 2021, 10(4), 381; https://doi.org/10.3390/antibiotics10040381 - 3 Apr 2021

Cited by 11 | Viewed by 3913

Abstract

Infections caused by nontuberculous mycobacteria (NTM) are increasing worldwide, resulting in a new global health concern. NTM treatment is complex and requires combinations of several drugs for lengthy periods. In spite of this, NTM disease is often associated with poor treatment outcomes. The anti-parasitic family of macrocyclic lactones (ML) (divided in two subfamilies: avermectins and milbemycins) was previously described as having activity against mycobacteria, including Mycobacterium tuberculosis, Mycobacterium ulcerans, and Mycobacterium marinum, among others. Here, we aimed to characterize the in vitro anti-mycobacterial activity of ML against a wide range of NTM species, including Mycobacteroides abscessus. For this, Minimum Inhibitory Concentration (MIC) values of eight ML were determined against 80 strains belonging to nine different NTM species. Macrocyclic lactones showed variable ranges of anti-mycobacterial activity that were compound and species-dependent. Milbemycin oxime was the most active compound, displaying broad-spectrum activity with MIC lower than 8 mg/L. Time kill assays confirmed MIC data and showed bactericidal and sterilizing activity of some compounds. Macrocyclic lactones are available in many formulations and have been extensively used in veterinary and human medicine with suitable pharmacokinetics and safety properties. This information could be exploited to explore repurposing of anti-helminthics for NTM therapy. Full article

(This article belongs to the Special Issue The Quest for Novel Antimicrobials: From Chemical Synthesis and Discovery to Mechanisms of Action and Resistance)

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8 pages, 1296 KiB

Open AccessArticle

Repurposing of the Tamoxifen Metabolites to Combat Infections by Multidrug-Resistant Gram-Negative Bacilli

by Andrea Miró-Canturri, Rafael Ayerbe-Algaba, Andrea Vila-Domínguez, Manuel E. Jiménez-Mejías, Jerónimo Pachón and Younes Smani

Antibiotics 2021, 10(3), 336; https://doi.org/10.3390/antibiotics10030336 - 22 Mar 2021

Cited by 8 | Viewed by 3562

Abstract

The development of new strategic antimicrobial therapeutic approaches, such as drug repurposing, has become an urgent need. Previously, we reported that tamoxifen presents therapeutic efficacy against multidrug-resistant (MDR) Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli in experimental infection models by modulating innate immune system cell traffic. The main objective of this study was to analyze the activity of N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen, three major metabolites of tamoxifen, against these pathogens. We showed that immunosuppressed mice infected with A. baumannii, P. aeruginosa, or E. coli in peritoneal sepsis models and treated with tamoxifen at 80 mg/kg/d for three days still reduced the bacterial load in tissues and blood. Moreover, it increased mice survival to 66.7% (for A. baumannii and E. coli) and 16.7% (for P. aeruginosa) when compared with immunocompetent mice. Further, susceptibility and time-kill assays showed that N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen exhibited minimum inhibitory concentration of the 90% of the isolates (MIC₉₀) values of 16 mg/L, and were bactericidal against clinical isolates of A. baumannii and E. coli. This antimicrobial activity of tamoxifen metabolites paralleled an increased membrane permeability of A. baumannii and E. coli without affecting their outer membrane proteins profiles. Together, these data showed that tamoxifen metabolites presented antibacterial activity against MDR A. baumannii and E. coli, and may be a potential alternative for the treatment of infections caused by these two pathogens. Full article

(This article belongs to the Special Issue The Quest for Novel Antimicrobials: From Chemical Synthesis and Discovery to Mechanisms of Action and Resistance)

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13 pages, 1127 KiB

Open AccessArticle

Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei

by Fátima Cerqueira, Marta Maia, Carla Gabriel, Rui Medeiros, Sara Cravo, Ana Isabel Ribeiro, Daniela Dantas, Alice Maria Dias, Lucília Saraiva, Liliana Raimundo and Eugénia Pinto

Antibiotics 2021, 10(2), 183; https://doi.org/10.3390/antibiotics10020183 - 12 Feb 2021

Cited by 19 | Viewed by 4697

Abstract

Systemic mycoses are one major cause of morbidity/mortality among immunocompromised/debilitated individuals. Studying the mechanism of action is a strategy to develop safer/potent antifungals, warning resistance emergence. The major goal of this study was to elucidate the mechanism of action of three (Z)-5-amino-N’-aryl-1-methyl-1H-imidazole-4-carbohydrazonamides (2h, 2k, 2l) that had previously demonstrated strong antifungal activity against Candida krusei and C. albicans ATCC strains. Activity was confirmed against clinical isolates, susceptible or resistant to fluconazole by broth microdilution assay. Ergosterol content (HPLC-DAD), mitochondrial dehydrogenase activity (MTT), reactive oxygen species (ROS) generation (flow cytometry), germ tube inhibition and drug interaction were evaluated. None of the compounds inhibited ergosterol synthesis. Ascorbic acid reduced the antifungal effect of compounds and significantly decreased ROS production. The metabolic viability of C. krusei was significantly reduced for values of 2MIC. Compounds 2h and 2k caused a significant increase in ROS production for MIC values while for 2l a significant increase was only observed for concentrations above MIC. ROS production seems to be involved in antifungal activity and the higher activity against C. krusei versus C. albicans may be related to their unequal sensitivity to different ROS. No synergism with fluconazole or amphotericin was observed, but the association of 2h with fluconazole might be valuable due to the significant inhibition of the dimorphic transition, a C. albicans virulence mechanism. Full article

(This article belongs to the Special Issue The Quest for Novel Antimicrobials: From Chemical Synthesis and Discovery to Mechanisms of Action and Resistance)

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31 pages, 7885 KiB

Open AccessArticle

Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors

by Ahmed Ragab, Sawsan A. Fouad, Ola A. Abu Ali, Entsar M. Ahmed, Abeer M. Ali, Ahmed A. Askar and Yousry A. Ammar

Antibiotics 2021, 10(2), 162; https://doi.org/10.3390/antibiotics10020162 - 5 Feb 2021

Cited by 55 | Viewed by 5476

Abstract

Herein, a series of novel hybrid sulfaguanidine moieties, bearing 2-cyanoacrylamide 2a–d, pyridine-2-one 3–10, and 2-imino-2H-chromene-3-carboxamide 11, 12 derivatives, were synthesized, and their structure confirmed by spectral data and elemental analysis. All the synthesized compounds showed moderate to good antimicrobial activity against eight pathogens. The most promising six derivatives, 2a, 2b, 2d, 3a, 8, and 11, revealed to be best in inhibiting bacterial and fungal growth, thus showing bactericidal and fungicidal activity. These derivatives exhibited moderate to potent inhibition against DNA gyrase and DHFR enzymes, with three derivatives 2d, 3a, and 2a demonstrating inhibition of DNA gyrase, with IC₅₀ values of 18.17–23.87 µM, and of DHFR, with IC₅₀ values of 4.33–5.54 µM; their potency is near to that of the positive controls. Further, the six derivatives exhibited immunomodulatory potential and three derivatives, 2d, 8, and 11, were selected for further study and displayed an increase in spleen and thymus weight and enhanced the activation of CD4⁺ and CD8⁺ T lymphocytes. Finally, molecular docking and some AMED studies were performed. Full article

(This article belongs to the Special Issue The Quest for Novel Antimicrobials: From Chemical Synthesis and Discovery to Mechanisms of Action and Resistance)

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14 pages, 4652 KiB

Open AccessEditor’s ChoiceArticle

Key Parameters on the Antibacterial Activity of Silver Camphor Complexes

by Joana P. Costa, Sílvia A. Sousa, Adelino M. Galvão, J. Miguel Mata, Jorge H. Leitão and M. Fernanda N. N. Carvalho

Antibiotics 2021, 10(2), 135; https://doi.org/10.3390/antibiotics10020135 - 30 Jan 2021

Cited by 13 | Viewed by 3666

Abstract

Nine new complexes with camphor imine or camphor sulfonimine ligands were synthesized and analytically and spectroscopically characterized, aiming to identify the key parameters that drive the antibacterial activity of the complexes with metal cores and imine substituents with distinct electronic and steric characteristics. The antimicrobial activity of all complexes was evaluated by determining their minimum inhibitory concentrations (MIC) against the Gram-negative Escherichia coli ATCC25922, Pseudomonas aeruginosa 477, and Burkholderia contaminans IST408, and the Gram-positive Staphylococcus aureus Newman. Camphor imine complexes based on the hydroxyl silver center ({Ag(OH)}) typically perform better than those based on the nitrate silver center ({Ag(NO₃)}), while ligands prone to establish hydrogen bonding facilitate interactions with the bacterial cell surface structures. A different trend is observed for the silver camphor sulfonimine complexes that are almost non-sensitive to the nature of the metal cores {Ag(OH)} or {Ag(NO₃)} and display low sensitivity to the Y substituent. The antibacterial activities of the Ag(I) camphor sulfonimine complexes are higher than those of the camphor imine analogues. All the complexes display higher activity towards Gram-negative strains than towards the Gram-positive strain. Full article

(This article belongs to the Special Issue The Quest for Novel Antimicrobials: From Chemical Synthesis and Discovery to Mechanisms of Action and Resistance)

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15 pages, 3375 KiB

Open AccessArticle

Electrodecoration and Characterization of Superparamagnetic Iron Oxide Nanoparticles with Bioactive Synergistic Nanocopper: Magnetic Hyperthermia-Induced Ionic Release for Anti-Biofilm Action

by Verdiana Marchianò, Maria Salvador, Amanda Moyano, Gemma Gutiérrez, María Matos, Susana Yáñez-Vilar, Yolanda Piñeiro, José Rivas, José C. Martínez-García, Davide Peddis, Maria C. Blanco-López, Montserrat Rivas, Nicoletta Ditaranto and Nicola Cioffi

Antibiotics 2021, 10(2), 119; https://doi.org/10.3390/antibiotics10020119 - 27 Jan 2021

Cited by 10 | Viewed by 3118

Abstract

The urgency for the availability of new antibacterial/disinfectant agents has become a worldwide priority. At the same time, along with the extensive use of other metal nanoparticles (NPs), the investigation of magnetic NPs (MNPs) in antibacterial studies has turned out to be an increasingly attractive research field. In this context, we present the preparation and characterization of superparamagnetic iron oxide NPs, electrodecorated with antimicrobial copper NPs, able to modulate the release of bioactive species not only by the NP’s stabilizer, but also through the application of a suitable magnetic field. Antimicrobial synergistic CuNPs stabilized by benzalkonium chloride have been used in the current study. We demonstrate the successful preparation of Cu@Fe₃O₄ MNPs composites through morphological and spectroscopic results. Additionally, an extensive magnetic characterization is reported, along with hyperthermia-induced copper ionic release. On the basis of our results, we propose a new generation of antimicrobial magnetic nanomaterials, whose bioactivity can be also tuned by the application of a magnetic field. Full article

(This article belongs to the Special Issue The Quest for Novel Antimicrobials: From Chemical Synthesis and Discovery to Mechanisms of Action and Resistance)

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12 pages, 671 KiB

Open AccessArticle

In Vitro Activities and Inoculum Effects of Ceftazidime-Avibactam and Aztreonam-Avibactam against Carbapenem-Resistant Enterobacterales Isolates from South Korea

by Taeeun Kim, Seung Cheol Lee, Moonsuk Bae, Heungsup Sung, Mi-Na Kim, Jiwon Jung, Min Jae Kim, Sung-Han Kim, Sang-Oh Lee, Sang-Ho Choi, Yang Soo Kim and Yong Pil Chong

Antibiotics 2020, 9(12), 912; https://doi.org/10.3390/antibiotics9120912 - 15 Dec 2020

Cited by 20 | Viewed by 3514

Abstract

Ceftazidime-avibactam (CAZ-AVI) and aztreonam-avibactam (AZT-AVI) are novel antibiotic combinations active against multidrug-resistant Gram-negative pathogens. This study aimed to evaluate their in vitro activities and inoculum effects in carbapenem-resistant Enterobacterales (CRE), including carbapenemase-producing (CP)-CRE and non-CP-CRE. A total of 81 independent clinical isolates of carbapenem-resistant Escherichia coli and Klebsiella pneumoniae were collected. CAZ-AVI and AZT-AVI minimal inhibitory concentrations (MICs) were evaluated by broth microdilution using standard and high inocula. The inoculum effect was defined as an ≥8-fold increase in MIC with high inoculum. Phenotypic determination of β-lactam resistance mechanism and PCR for carbapenemase genes were performed. Of the 81 CRE isolates, 35 (43%) were CP-CRE. Overall, 73% of the isolates were susceptible to CAZ-AVI, and 95% had low AZT-AVI MICs (≤8 µg/mL). The MIC_50/MIC₉₀s of CAZ-AVI and AZT-AVI were 4/≥512 µg/mL and 0.5/4 µg/mL, respectively. CAZ-AVI was more active against non-CP-CRE than against CP-CRE (susceptibility 80% vs. 63%, p = 0.08; MIC₅₀/MIC₉₀, 2/16 μg/mL vs. 4/≥512 μg/mL), whereas AZT-AVI was more active against CP-CRE (MIC₅₀/MIC₉₀, 0.25/1 μg/mL vs. 0.5/8 μg/mL). All four isolates with high AZT-AVI MIC (≥16 μg/mL) were resistant to CAZ-AVI, but only 18% (4/22) of CAZ-AVI-resistant isolates had high AZT-AVI MIC. The rates of the inoculum effect for CAZ-AVI and AZT-AVI were 18% and 47%, respectively (p < 0.001). Interestingly, the frequency of the AZT-AVI inoculum effect was higher in K. pneumoniae than E. coli (64% vs. 8%, p < 0.001). AZT-AVI is more active against CRE than CAZ-AVI, even in CP-CRE and CAZ-AVI-resistant isolates. The presence of a substantial inoculum effect may contribute to clinical failure in high-inoculum infections treated with AZT-AVI. Full article

(This article belongs to the Special Issue The Quest for Novel Antimicrobials: From Chemical Synthesis and Discovery to Mechanisms of Action and Resistance)

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15 pages, 3024 KiB

Open AccessArticle

Stress-Based High-Throughput Screening Assays to Identify Inhibitors of Cell Envelope Biogenesis

by Maurice Steenhuis, Corinne M. ten Hagen-Jongman, Peter van Ulsen and Joen Luirink

Antibiotics 2020, 9(11), 808; https://doi.org/10.3390/antibiotics9110808 - 13 Nov 2020

Cited by 16 | Viewed by 3630

Abstract

The structural integrity of the Gram-negative cell envelope is guarded by several stress responses, such as the σ^E, Cpx and Rcs systems. Here, we report on assays that monitor these responses in E. coli upon addition of antibacterial compounds. Interestingly, compromised peptidoglycan synthesis, outer membrane biogenesis and LPS integrity predominantly activated the Rcs response, which we developed into a robust HTS (high-throughput screening) assay that is suited for phenotypic compound screening. Furthermore, by interrogating all three cell envelope stress reporters, and a reporter for the cytosolic heat-shock response as control, we found that inhibitors of specific envelope targets induce stress reporter profiles that are distinct in quality, amplitude and kinetics. Finally, we show that by using a host strain with a more permeable outer membrane, large-scaffold antibiotics can also be identified by the reporter assays. Together, the data suggest that stress profiling is a useful first filter for HTS aimed at inhibitors of cell envelope processes. Full article

(This article belongs to the Special Issue The Quest for Novel Antimicrobials: From Chemical Synthesis and Discovery to Mechanisms of Action and Resistance)

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