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Antibiotics
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Chemical Tools for Antibiotics Research
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Chemical Tools for Antibiotics Research

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (1 September 2019) | Viewed by 55423

Special Issue Editor

Prof. Dr. Gerd Wagner

E-Mail Website
Guest Editor
School of Pharmacy, Queen’s University Belfast, Belfast, UK
Interests: medicinal chemistry; chemical biology; carbohydrate and nucleotide chemistry; enzyme inhibitors; antimicrobial resistance; bioassays; glycobiology; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Antimicrobial resistance is a growing threat to human and animal health. Bacterial strains that are resistant to antibiotics of last resort, including Klebsiella pneumoniae and Neisseria gonorrhoea, are emerging at an alarming rate. The discovery of new antibiotics is therefore an urgent scientific and technological challenge.

This Special Issue showcases recent examples of chemical tools to address this challenge.

Chemical tools such as small molecule inhibitors and probes occupy a unique place in the arsenal of techniques to study biological systems. They can be used for the mechanistic and structural characterisation of individual proteins, but also for the proteome-wide interrogation of an entire organism. Chemical tools allow reversible, dose- and time-dependent interventions in a manner that few other techniques can, but also permanent labelling experiments in intact cells. They are powerful tools for target identification and validation studies, and can themselves serve as chemical starting points for antibiotics discovery.

Perhaps one of the most exciting features of chemical tools is their applicability across species boundaries, with wild-type bacteria and clinical strains. This Special Issue brings together recent case studies of chemical tools in antibiotics research with different pathogens—not least in the hope that it will promote the availability of these tools to a wide audience across the microbiology, infectious disease and drug discovery communities.

Dr. Gerd Wagner
Guest Editor

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

  • Chemical tool
  • enzyme inhibitor
  • small molecule
  • molecular probe
  • antimicrobial resistance
  • antibiotics

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Published Papers (7 papers)

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Research

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23 pages, 1525 KiB  
Article
Synthesis and Biological Evaluation of Lipophilic Nucleoside Analogues as Inhibitors of Aminoacyl-tRNA Synthetases
by Manesh Nautiyal, Bharat Gadakh, Steff De Graef, Luping Pang, Masroor Khan, Yi Xun, Jef Rozenski and Arthur Van Aerschot
Antibiotics 2019, 8(4), 180; https://doi.org/10.3390/antibiotics8040180 - 9 Oct 2019
Cited by 2 | Viewed by 4719
Abstract
Emerging antibiotic resistance in pathogenic bacteria and reduction of compounds in the existing antibiotics discovery pipeline is the most critical concern for healthcare professionals. A potential solution aims to explore new or existing targets/compounds. Inhibition of bacterial aminoacyl-tRNA synthetase (aaRSs) could be one [...] Read more.
Emerging antibiotic resistance in pathogenic bacteria and reduction of compounds in the existing antibiotics discovery pipeline is the most critical concern for healthcare professionals. A potential solution aims to explore new or existing targets/compounds. Inhibition of bacterial aminoacyl-tRNA synthetase (aaRSs) could be one such target for the development of antibiotics. The aaRSs are a group of enzymes that catalyze the transfer of an amino acid to their cognate tRNA and therefore play a pivotal role in translation. Thus, selective inhibition of these enzymes could be detrimental to microbes. The 5′-O-(N-(L-aminoacyl)) sulfamoyladenosines (aaSAs) are potent inhibitors of the respective aaRSs, however due to their polarity and charged nature they cannot cross the bacterial membranes. In this work, we increased the lipophilicity of these existing aaSAs in an effort to promote their penetration through the bacterial membrane. Two strategies were followed, either attaching a (permanent) alkyl moiety at the adenine ring via alkylation of the N6-position or introducing a lipophilic biodegradable prodrug moiety at the alpha-terminal amine, totaling eight new aaSA analogues. All synthesized compounds were evaluated in vitro using either a purified Escherichia coli aaRS enzyme or in presence of total cellular extract obtained from E. coli. The prodrugs showed comparable inhibitory activity to the parent aaSA analogues, indicating metabolic activation in cellular extracts, but had little effect on bacteria. During evaluation of the N6-alkylated compounds against different microbes, the N6-octyl containing congener 6b showed minimum inhibitory concentration (MIC) of 12.5 µM against Sarcina lutea while the dodecyl analogue 6c displayed MIC of 6.25 µM against Candida albicans. Full article
(This article belongs to the Special Issue Chemical Tools for Antibiotics Research)
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11 pages, 583 KiB  
Article
Synthesis of Ring II/III Fragment of Kanamycin: A New Minimum Structural Motif for Aminoglycoside Recognition
by Sandra G. Zárate, Agatha Bastida, Andrés G. Santana and Julia Revuelta
Antibiotics 2019, 8(3), 109; https://doi.org/10.3390/antibiotics8030109 - 2 Aug 2019
Cited by 2 | Viewed by 4046
Abstract
A novel protocol has been established to prepare the kanamycin ring II/III fragment, which has been validated as a minimum structural motif for the development of new aminoglycosides on the basis of its bactericidal activity even against resistant strains. Furthermore, its ability to [...] Read more.
A novel protocol has been established to prepare the kanamycin ring II/III fragment, which has been validated as a minimum structural motif for the development of new aminoglycosides on the basis of its bactericidal activity even against resistant strains. Furthermore, its ability to act as a AAC-(6′) and APH-(3′) binder, and as a poor substrate for the ravenous ANT-(4′), makes it an excellent candidate for the design of inhibitors of these aminoglycoside modifying enzymes. Full article
(This article belongs to the Special Issue Chemical Tools for Antibiotics Research)
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11 pages, 10823 KiB  
Article
A Molecular Modeling Approach to Identify Novel Inhibitors of the Major Facilitator Superfamily of Efflux Pump Transporters
by Sandra G. Zárate, Paula Morales, Katarzyna Świderek, Victor M. Bolanos-Garcia and Agatha Bastida
Antibiotics 2019, 8(1), 25; https://doi.org/10.3390/antibiotics8010025 - 15 Mar 2019
Cited by 32 | Viewed by 7050
Abstract
Multidrug efflux systems play a prominent role in medicine, as they are important contributors to bacterial antibiotic resistance. NorA is an efflux pump transporter from the major facilitator superfamily that expels numerous drug compounds across the inner membrane of Staphylococcus aureus (S. [...] Read more.
Multidrug efflux systems play a prominent role in medicine, as they are important contributors to bacterial antibiotic resistance. NorA is an efflux pump transporter from the major facilitator superfamily that expels numerous drug compounds across the inner membrane of Staphylococcus aureus (S. aureus). The design of novel inhibitors to combat drug efflux could offer new opportunities to avoid the problem of antibiotic resistance. In this study, we performed molecular modeling studies in an effort to discover novel NorA efflux pump inhibitors. A group of over 673 compounds from the PubChem database with a high (>80%) level of similarity to the chemical structure of capsaicin was used to study the binding affinity of small molecule compounds for the NorA efflux pump. Ten potential lead compounds displayed a good druggability profile, with one in particular (CID 44330438) providing new insight into the molecular mechanism of the inhibition of major facilitator superfamily (MFS) efflux pump transporters. It is our hope that the overall strategy described in this study, and the structural information of the potential novel inhibitors thus identified, will stimulate others to pursue the development of better drugs to tackle multidrug resistance in S. aureus. Full article
(This article belongs to the Special Issue Chemical Tools for Antibiotics Research)
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15 pages, 2685 KiB  
Article
The Effects of Mentha × piperita Essential Oil on C. albicans Growth, Transition, Biofilm Formation, and the Expression of Secreted Aspartyl Proteinases Genes
by Chahrazed Benzaid, Amine Belmadani, Ryad Djeribi and Mahmoud Rouabhia
Antibiotics 2019, 8(1), 10; https://doi.org/10.3390/antibiotics8010010 - 30 Jan 2019
Cited by 35 | Viewed by 6857
Abstract
The rise in resistance and changes in the spectrum of Candida infections have generated enormous interest in developing new antifungal drugs using natural molecules such as plant essential oils (EOs). Antimicrobial activity against foodborne pathogenic and spoilage microorganisms has been reported for EOs. [...] Read more.
The rise in resistance and changes in the spectrum of Candida infections have generated enormous interest in developing new antifungal drugs using natural molecules such as plant essential oils (EOs). Antimicrobial activity against foodborne pathogenic and spoilage microorganisms has been reported for EOs. The goal of this study was to assess the effect of Mentha × piperita essential oil (EO) on C. albicans growth, transition (change from blastospore to hyphae forms), and biofilm formation as well as on the expression of certain virulent genes. We show that whole EO and its vapor attenuated the yeast’s growth, compared to that in the control. The effect of the EO was comparable to that of amphotericin-B (AmB). The EO and its vapor significantly decreased the morphological changes of C. albicans, reduced biofilm formation, and disrupted mature C. albicans biofilms. The effect produced by whole EO on biofilm formation/disruption was notably comparable to that observed with AmB. Exposure of C. albicans to EO and its vapor downregulated the expression of various genes, such as secreted aspartyl proteinases (SAP 1, 2, 3, 9, 10) and hyphal wall protein 1 (HWP1). Altogether, these results provide new insight into the efficacy of Mentha × piperita EO against C. albicans and suggest the potential of Mentha × piperita EO for use as an antifungal therapy in multiple applications. Full article
(This article belongs to the Special Issue Chemical Tools for Antibiotics Research)
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14 pages, 3108 KiB  
Article
Induction of Biofilm Formation in Klebsiella pneumoniae ATCC 13884 by Several Drugs: The Possible Role of Quorum Sensing Modulation
by Elizabeth Cadavid, Sara M. Robledo, Wiston Quiñones and Fernando Echeverri
Antibiotics 2018, 7(4), 103; https://doi.org/10.3390/antibiotics7040103 - 28 Nov 2018
Cited by 15 | Viewed by 5229
Abstract
Bacterial resistance is caused by several biochemical factors, the formation of biofilm being one of the main causes. This process is triggered by Quorum Sensing (QS), through the production of endogenous molecules, although other substances such as natural products can also [...] Read more.
Bacterial resistance is caused by several biochemical factors, the formation of biofilm being one of the main causes. This process is triggered by Quorum Sensing (QS), through the production of endogenous molecules, although other substances such as natural products can also do this. In this work, we aimed to determine whether some drugs are involved in the induction of biofilm formation in Klebsiella pneumoniae ATCC 13884, and thus, increase bacterial resistance. For this, the effect of 22 drugs on K. pneumoniae ATCC 13884 growth was determined at sub-plasmatic concentrations; the production of autoinducer lactones was established by HPLC and with a biosensor. The induction of biofilm formation was determined through crystal violet assay at 585 nm in a microplate reader and using urethral catheters. According to the in vitro assays, some drugs were found to induce biofilm formation in K. pneumoniae ATCC 13884. The effect of acetaminophen, hydrochlorothiazide, and progesterone stood out. The first drug caused several changes in the biochemistry of K. pneumoniae ATCC 13884 related to QS: high synthesis of N-hexanoyl-homoserine lactone, increasing bacterial populations by 27% and biofilm formation by 49%, and a more gentamicin resistant biofilm. Furthermore, it increased the colonization area of urethral catheters. Hydrochlorothiazide showed the biggest increase in the induction of biofilm formation of 51%, and progesterone displayed the greatest ability to provoke bacterial mass adherence but had no effects on K. pneumoniae ATCC 13884 bacterial population growth. Full article
(This article belongs to the Special Issue Chemical Tools for Antibiotics Research)
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Review

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29 pages, 3060 KiB  
Review
Recent Progress in the Development of Small-Molecule FtsZ Inhibitors as Chemical Tools for the Development of Novel Antibiotics
by Laura Carro
Antibiotics 2019, 8(4), 217; https://doi.org/10.3390/antibiotics8040217 - 11 Nov 2019
Cited by 33 | Viewed by 6226
Abstract
Antibiotics are potent pharmacological weapons against bacterial pathogens, nevertheless their efficacy is becoming compromised due to the worldwide emergence and spread of multidrug-resistant bacteria or “superbugs”. Antibiotic resistance is rising to such dangerous levels that the treatment of bacterial infections is becoming a [...] Read more.
Antibiotics are potent pharmacological weapons against bacterial pathogens, nevertheless their efficacy is becoming compromised due to the worldwide emergence and spread of multidrug-resistant bacteria or “superbugs”. Antibiotic resistance is rising to such dangerous levels that the treatment of bacterial infections is becoming a clinical challenge. Therefore, urgent action is needed to develop new generations of antibiotics that will help tackle this increasing and serious public health problem. Due to its essential role in bacterial cell division, the tubulin-like protein FtsZ has emerged as a promising target for the development of novel antibiotics with new mechanisms of action. This review highlights the medicinal chemistry efforts towards the identification of small-molecule FtsZ inhibitors with antibacterial activity in the last three years. Full article
(This article belongs to the Special Issue Chemical Tools for Antibiotics Research)
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25 pages, 830 KiB  
Review
CRISPR-Cas: Converting A Bacterial Defence Mechanism into A State-of-the-Art Genetic Manipulation Tool
by Alexandre Loureiro and Gabriela Jorge da Silva
Antibiotics 2019, 8(1), 18; https://doi.org/10.3390/antibiotics8010018 - 28 Feb 2019
Cited by 60 | Viewed by 20269
Abstract
Bacteriophages are pervasive viruses that infect bacteria, relying on their genetic machinery to replicate. In order to protect themselves from this kind of invader, bacteria developed an ingenious adaptive defence system, clustered regularly interspaced short palindromic repeats (CRISPR). Researchers soon realised that a [...] Read more.
Bacteriophages are pervasive viruses that infect bacteria, relying on their genetic machinery to replicate. In order to protect themselves from this kind of invader, bacteria developed an ingenious adaptive defence system, clustered regularly interspaced short palindromic repeats (CRISPR). Researchers soon realised that a specific type of CRISPR system, CRISPR-Cas9, could be modified into a simple and efficient genetic engineering technology, with several improvements over currently used systems. This discovery set in motion a revolution in genetics, with new and improved CRISPR systems being used in plenty of in vitro and in vivo experiments in recent years. This review illustrates the mechanisms behind CRISPR-Cas systems as a means of bacterial immunity against phage invasion and how these systems were engineered to originate new genetic manipulation tools. Newfound CRISPR-Cas technologies and the up-and-coming applications of these systems on healthcare and other fields of science are also discussed. Full article
(This article belongs to the Special Issue Chemical Tools for Antibiotics Research)
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