Finding Innovative Targets and Mechanisms While Discovering Novel Antimicrobial Agents

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Mechanisms and Structural Biology of Antibiotic Action".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 35791

Special Issue Editor


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Guest Editor
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Luigi Mangiagalli, 25, 20133 Milan, Italy
Interests: drug discovery; medicinal chemistry, structure activity relationship; development of novel antimicrobials; FtsZ inhibitors; RnpA inhibitors; inhibition of bacterial cellular division process
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Special Issue Information

Dear Colleagues,

Antimicrobial resistance remains a critical and urgent need for public health, and the actual COVID-19 pandemic has further stressed this serious problem.

Among the most common multidrug-resistant bacteria, the acronym ESKAPE was ad hoc invented, referring to the most virulent and antibiotic-resistant pathogen strains: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. These Gram-positive and Gram-negative strains are the major cause of life-threatening infections.

The general inefficacy of commonly used antibiotics raises the importance of developing new antibacterial agents having an innovative and effective mechanism of action, able to counter the emergence of resistance.

With this Special Issue, all scientists working on antimicrobial agents, specifically those focusing on innovative targets and mechanisms of action, in infectious diseases caused by bacteria, parasites, viruses, and fungi are invited to contribute submissions. All manuscripts dealing with the design and synthesis, biological evaluation, and target validation of novel antimicrobials are welcome, as well as reviews or short communications.

Dr. Valentina Straniero
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

  • antibacterial agents
  • antimicrobial resistance
  • multidrug resistance
  • antimicrobial targets
  • mechanisms of action
  • target validation
  • drug discovery
  • drug repurposing
  • medicinal chemistry

Published Papers (12 papers)

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Editorial

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4 pages, 170 KiB  
Editorial
Finding Ways to Fight Antimicrobial Resistance: Present, Future, and Perspectives
by Valentina Straniero
Antibiotics 2024, 13(2), 171; https://doi.org/10.3390/antibiotics13020171 - 9 Feb 2024
Viewed by 1393
Abstract
Antimicrobial resistance (AMR) is a worldwide severe topic, affecting both human and animal health [...] Full article

Research

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23 pages, 3506 KiB  
Article
Benzodioxane–Benzamides as FtsZ Inhibitors: Effects of Linker’s Functionalization on Gram-Positive Antimicrobial Activity
by Lorenzo Suigo, William Margolin, Eugenia Ulzurrun, Martina Hrast Rambaher, Carlo Zanotto, Victor Sebastián-Pérez, Nuria E. Campillo, Valentina Straniero and Ermanno Valoti
Antibiotics 2023, 12(12), 1712; https://doi.org/10.3390/antibiotics12121712 - 8 Dec 2023
Cited by 2 | Viewed by 1101
Abstract
FtsZ is an essential bacterial protein abundantly studied as a novel and promising target for antimicrobials. FtsZ is highly conserved among bacteria and mycobacteria, and it is crucial for the correct outcome of the cell division process, as it is responsible for the [...] Read more.
FtsZ is an essential bacterial protein abundantly studied as a novel and promising target for antimicrobials. FtsZ is highly conserved among bacteria and mycobacteria, and it is crucial for the correct outcome of the cell division process, as it is responsible for the division of the parent bacterial cell into two daughter cells. In recent years, the benzodioxane–benzamide class has emerged as very promising and capable of targeting both Gram-positive and Gram-negative FtsZs. In this study, we explored the effect of including a substituent on the ethylenic linker between the two main moieties on the antimicrobial activity and pharmacokinetic properties. This substitution, in turn, led to the generation of a second stereogenic center, with both erythro and threo isomers isolated, characterized, and evaluated. With this work, we discovered how the hydroxy group slightly affects the antimicrobial activity, while being an important anchor for the exploitation and development of prodrugs, probes, and further derivatives. Full article
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10 pages, 1175 KiB  
Communication
An Initial Report of the Antimicrobial Activities of Volatiles Produced during Rapid Volatilization of Oils
by Sangeetha Ramamurthy, Jonathan Kopel, David Westenberg and Shubhender Kapila
Antibiotics 2022, 11(12), 1742; https://doi.org/10.3390/antibiotics11121742 - 2 Dec 2022
Cited by 1 | Viewed by 1246
Abstract
Aerosols generated through volatilization and subsequent recondensation of oil vapors have been used as obscurant (smoke) screens during military operations since the early twentieth century. Specifically, a petroleum middle distillate known as the fog oil (FO) has been used in US military battlefields [...] Read more.
Aerosols generated through volatilization and subsequent recondensation of oil vapors have been used as obscurant (smoke) screens during military operations since the early twentieth century. Specifically, a petroleum middle distillate known as the fog oil (FO) has been used in US military battlefields to create obscurant smoke screens. During a study on the feasibility of replacing petroleum-derived FO with vegetable oil-derived esters such as methyl soyate (MS), it was observed that that FO and MS aerosols and vapors did not exhibit detectable mutagenic activity but were lethal to Ames strains bacteria even after very short exposure periods. These results opened the potential use of oil-derived vapors as antimicrobial agents. Subsequent studies showed that optimal aerosol/vapor production conditions could further enhance disinfectant efficiency. For this purpose, we examined the antimicrobial activities of mineral oils and biogenic oil ester aerosols/vapors against a wide range of Gram-positive and Gram-negative bacteria. The results of the study showed that the aerosols/vapors obtained from mineral oil or vegetable oil ester under proper conditions can serve as an excellent antibacterial disinfectant. Full article
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13 pages, 1268 KiB  
Article
Targeting SAM-I Riboswitch Using Antisense Oligonucleotide Technology for Inhibiting the Growth of Staphylococcus aureus and Listeria monocytogenes
by Martina Traykovska and Robert Penchovsky
Antibiotics 2022, 11(11), 1662; https://doi.org/10.3390/antibiotics11111662 - 19 Nov 2022
Cited by 10 | Viewed by 1793
Abstract
With the discovery of antibiotics, a productive period of antibacterial drug innovation and application in healthcare systems and agriculture resulted in saving millions of lives. Unfortunately, the misusage of antibiotics led to the emergence of many resistant pathogenic strains. Some riboswitches have risen [...] Read more.
With the discovery of antibiotics, a productive period of antibacterial drug innovation and application in healthcare systems and agriculture resulted in saving millions of lives. Unfortunately, the misusage of antibiotics led to the emergence of many resistant pathogenic strains. Some riboswitches have risen as promising targets for developing antibacterial drugs. Here, we describe the design and applications of the chimeric antisense oligonucleotide (ASO) as a novel antibacterial agent. The pVEC-ASO-1 consists of a cell-penetrating oligopeptide known as pVEC attached to an oligonucleotide part with modifications of the first and the second generations. This combination of modifications enables specific mRNA degradation under multiple turnover conditions via RNase H. The pVEC-ASO targets the S-adenosyl methionine (SAM)-I riboswitch found in the genome of many Gram-positive bacteria. The SAM-I riboswitch controls not only the biosynthesis but also the transport of SAM. We have established an antibiotic dosage of 700 nM (4.5 µg/mL) of pVEC-ASO that inhibits 80% of the growth of Staphylococcus aureus and Listeria monocytogenes. The pVEC-ASO-1 does not show any toxicity in the human cell line at MIC80’s concentration. We have proven that the SAM-I riboswitch is a suitable target for antibacterial drug development based on ASO. The approach is rational and easily adapted to other bacterial RNA targets. Full article
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25 pages, 1647 KiB  
Article
Bioinformatics and Genomic Analyses of the Suitability of Eight Riboswitches for Antibacterial Drug Targets
by Nikolet Pavlova and Robert Penchovsky
Antibiotics 2022, 11(9), 1177; https://doi.org/10.3390/antibiotics11091177 - 31 Aug 2022
Cited by 6 | Viewed by 2513
Abstract
Antibiotic resistance (AR) is an acute problem that results in prolonged and debilitating illnesses. AR mortality worldwide is growing and causes a pressing need to research novel mechanisms of action and untested target molecules. This article presents in silico analyses of eight bacterial [...] Read more.
Antibiotic resistance (AR) is an acute problem that results in prolonged and debilitating illnesses. AR mortality worldwide is growing and causes a pressing need to research novel mechanisms of action and untested target molecules. This article presents in silico analyses of eight bacterial riboswitches for their suitability for antibacterial drug targets. Most bacterial riboswitches are located in the 5′-untranslated region of messenger RNAs, act as allosteric cis-acting gene control elements, and have not been found in humans before. Sensing metabolites, the riboswitches regulate the synthesis of vital cellular metabolites in various pathogenic bacteria. The analyses performed in this article represent a complete and informative genome-wide bioinformatics analysis of the adequacy of eight riboswitches as antibacterial drug targets in different pathogenic bacteria based on four criteria. Due to the ability of the riboswitch to control biosynthetic pathways and transport proteins of essential metabolites and the presence/absence of alternative biosynthetic pathways, we classified them into four groups based on their suitability for use as antibacterial drug targets guided by our in silico analyses. We concluded that some of them are promising targets for antibacterial drug discovery, such as the PreQ1, MoCo RNA, cyclic-di-GMP I, and cyclic-di-GMP II riboswitches. Full article
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20 pages, 6699 KiB  
Article
Halogenated Pyrrolopyrimidines with Low MIC on Staphylococcus aureus and Synergistic Effects with an Antimicrobial Peptide
by Cecilie Elisabeth Olsen, Fredrik Heen Blindheim, Caroline Krogh Søgaard, Lisa Marie Røst, Amanda Holstad Singleton, Olaug Elisabeth Torheim Bergum, Per Bruheim, Marit Otterlei, Eirik Sundby and Bård Helge Hoff
Antibiotics 2022, 11(8), 984; https://doi.org/10.3390/antibiotics11080984 - 22 Jul 2022
Cited by 5 | Viewed by 2090
Abstract
Currently, there is a world-wide rise in antibiotic resistance causing burdens to individuals and public healthcare systems. At the same time drug development is lagging behind. Therefore, finding new ways of treating bacterial infections either by identifying new agents or combinations of drugs [...] Read more.
Currently, there is a world-wide rise in antibiotic resistance causing burdens to individuals and public healthcare systems. At the same time drug development is lagging behind. Therefore, finding new ways of treating bacterial infections either by identifying new agents or combinations of drugs is of utmost importance. Additionally, if combination therapy is based on agents with different modes of action, resistance is less likely to develop. The synthesis of 21 fused pyrimidines and a structure-activity relationship study identified two 6-aryl-7H-pyrrolo [2,3-d] pyrimidin-4-amines with potent activity towards Staphylococcus aureus. The MIC-value was found to be highly dependent on a bromo or iodo substitution in the 4-benzylamine group and a hydroxyl in the meta or para position of the 6-aryl unit. The most active bromo and iodo derivatives had MIC of 8 mg/L. Interestingly, the most potent compounds experienced a four-fold lower MIC-value when they were combined with the antimicrobial peptide betatide giving MIC of 1–2 mg/L. The front runner bromo derivative also has a low activity towards 50 human kinases, including thymidylate monophosphate kinase, a putative antibacterial target. Full article
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Review

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17 pages, 1083 KiB  
Review
Targeting the Impossible: A Review of New Strategies against Endospores
by Alba Romero-Rodríguez, Beatriz Ruiz-Villafán, Claudia Fabiola Martínez-de la Peña and Sergio Sánchez
Antibiotics 2023, 12(2), 248; https://doi.org/10.3390/antibiotics12020248 - 26 Jan 2023
Cited by 4 | Viewed by 3792
Abstract
Endospore-forming bacteria are ubiquitous, and their endospores can be present in food, in domestic animals, and on contaminated surfaces. Many spore-forming bacteria have been used in biotechnological applications, while others are human pathogens responsible for a wide range of critical clinical infections. Due [...] Read more.
Endospore-forming bacteria are ubiquitous, and their endospores can be present in food, in domestic animals, and on contaminated surfaces. Many spore-forming bacteria have been used in biotechnological applications, while others are human pathogens responsible for a wide range of critical clinical infections. Due to their resistant properties, it is challenging to eliminate spores and avoid the reactivation of latent spores that may lead to active infections. Furthermore, endospores play an essential role in the survival, transmission, and pathogenesis of some harmful strains that put human and animal health at risk. Thus, different methods have been applied for their eradication. Nevertheless, natural products are still a significant source for discovering and developing new antibiotics. Moreover, targeting the spore for clinical pathogens such as Clostridioides difficile is essential to disease prevention and therapeutics. These strategies could directly aim at the structural components of the spore or their germination process. This work summarizes the current advances in upcoming strategies and the development of natural products against endospores. This review also intends to highlight future perspectives in research and applications. Full article
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24 pages, 66232 KiB  
Review
Microbial Genomics: Innovative Targets and Mechanisms
by Asma Hussain Alkatheri, Polly Soo-Xi Yap, Aisha Abushelaibi, Kok-Song Lai, Wan-Hee Cheng and Swee-Hua Erin Lim
Antibiotics 2023, 12(2), 190; https://doi.org/10.3390/antibiotics12020190 - 17 Jan 2023
Cited by 1 | Viewed by 3404
Abstract
Multidrug resistance (MDR) has become an increasing threat to global health because bacteria can develop resistance to antibiotics over time. Scientists worldwide are searching for new approaches that go beyond traditional antibiotic discovery and development pipelines. Advances in genomics, however, opened up an [...] Read more.
Multidrug resistance (MDR) has become an increasing threat to global health because bacteria can develop resistance to antibiotics over time. Scientists worldwide are searching for new approaches that go beyond traditional antibiotic discovery and development pipelines. Advances in genomics, however, opened up an unexplored therapeutic opportunity for the discovery of new antibacterial agents. Genomic approaches have been used to discover several novel antibiotics that target critical processes for bacterial growth and survival, including histidine kinases (HKs), LpxC, FabI, peptide deformylase (PDF), and aminoacyl-tRNA synthetases (AaRS). In this review, we will discuss the use of microbial genomics in the search for innovative and promising drug targets as well as the mechanisms of action for novel antimicrobial agents. We will also discuss future directions on how the utilization of the microbial genomics approach could improve the odds of antibiotic development having a more successful outcome. Full article
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13 pages, 632 KiB  
Review
The In Vivo and In Vitro Assessment of Pyocins in Treating Pseudomonas aeruginosa Infections
by Abdulaziz Alqahtani, Jonathan Kopel and Abdul Hamood
Antibiotics 2022, 11(10), 1366; https://doi.org/10.3390/antibiotics11101366 - 7 Oct 2022
Cited by 4 | Viewed by 2058
Abstract
Pseudomonas aeruginosa can cause several life-threatening infections among immunocompromised patients (e.g., cystic fibrosis) due to its ability to adapt and develop resistance to several antibiotics. In recent years, P. aeruginosa infections has become difficult to treat using conventional antibiotics due to the increase [...] Read more.
Pseudomonas aeruginosa can cause several life-threatening infections among immunocompromised patients (e.g., cystic fibrosis) due to its ability to adapt and develop resistance to several antibiotics. In recent years, P. aeruginosa infections has become difficult to treat using conventional antibiotics due to the increase multidrug-resistant P. aeruginosa strains. Therefore, there is a growing interest to develop novel treatments against antibiotic-resistance P. aeruginosa strains. One novel method includes the application of antimicrobial peptides secreted by P. aeruginosa strains, known as pyocins. In this review, we will discuss the structure, function, and use of pyocins in the pathogenesis and treatment of P. aeruginosa infection. Full article
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12 pages, 940 KiB  
Review
Occidiofungin: Actin Binding as a Novel Mechanism of Action in an Antifungal Agent
by Nopakorn Hansanant and Leif Smith
Antibiotics 2022, 11(9), 1143; https://doi.org/10.3390/antibiotics11091143 - 23 Aug 2022
Cited by 2 | Viewed by 2253
Abstract
The identification and development of natural products into novel antimicrobial agents is crucial to combat the rise of multidrug-resistant microorganisms. Clinical fungal isolates have been identified, which have shown resistance to all current clinical antifungals, highlighting a significant need to develop a novel [...] Read more.
The identification and development of natural products into novel antimicrobial agents is crucial to combat the rise of multidrug-resistant microorganisms. Clinical fungal isolates have been identified, which have shown resistance to all current clinical antifungals, highlighting a significant need to develop a novel antifungal agent. One of the natural products produced by the bacterium Burkholderia contaminans MS14 is the glycolipopeptide occidiofungin. Occidiofungin has demonstrated in vitro activity against a multitude of fungal species, including multidrug-resistant Candida auris strains, and in vivo effectiveness in treating vulvovaginal candidiasis. Characterization of occidiofungin revealed the mechanism of action as binding to actin to disrupt higher-order actin-mediated functions leading to the induction of apoptosis in fungal cells. Occidiofungin is the first small molecule capable of disrupting higher-order actin functions and is a first-in-class compound that is able to circumvent current antifungal resistant mechanisms by fungal species. Anticancer properties and antiparasitic activities, against Cryptosporidium parvum, have also been demonstrated in vitro. The novel mechanism of action and wide spectrum of activity highlights the potential of occidiofungin to be developed for clinical use. Full article
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21 pages, 4898 KiB  
Review
Chelation in Antibacterial Drugs: From Nitroxoline to Cefiderocol and Beyond
by Davorka Repac Antić, Marijo Parčina, Ivana Gobin and Mirna Petković Didović
Antibiotics 2022, 11(8), 1105; https://doi.org/10.3390/antibiotics11081105 - 15 Aug 2022
Cited by 14 | Viewed by 4655
Abstract
In the era of escalating antimicrobial resistance, the need for antibacterial drugs with novel or improved modes of action (MOAs) is a health concern of utmost importance. Adding or improving the chelating abilities of existing drugs or finding new, nature-inspired chelating agents seems [...] Read more.
In the era of escalating antimicrobial resistance, the need for antibacterial drugs with novel or improved modes of action (MOAs) is a health concern of utmost importance. Adding or improving the chelating abilities of existing drugs or finding new, nature-inspired chelating agents seems to be one of the major ways to ensure progress. This review article provides insight into the modes of action of antibacterial agents, class by class, through the perspective of chelation. We covered a wide scope of antibacterials, from a century-old quintessential chelating agent nitroxoline, currently unearthed due to its newly discovered anticancer and antibiofilm activities, over the commonly used antibacterial classes, to new cephalosporin cefiderocol and a potential future class of tetramates. We show the impressive spectrum of roles that chelation plays in antibacterial MOAs. This, by itself, demonstrates the importance of understanding the fundamental chemistry behind such complex processes. Full article
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18 pages, 381 KiB  
Review
Bacterial Multidrug Efflux Pumps at the Frontline of Antimicrobial Resistance: An Overview
by Lulu Huang, Cuirong Wu, Haijiao Gao, Chao Xu, Menghong Dai, Lingli Huang, Haihong Hao, Xu Wang and Guyue Cheng
Antibiotics 2022, 11(4), 520; https://doi.org/10.3390/antibiotics11040520 - 13 Apr 2022
Cited by 52 | Viewed by 8404
Abstract
Multidrug efflux pumps function at the frontline to protect bacteria against antimicrobials by decreasing the intracellular concentration of drugs. This protective barrier consists of a series of transporter proteins, which are located in the bacterial cell membrane and periplasm and remove diverse extraneous [...] Read more.
Multidrug efflux pumps function at the frontline to protect bacteria against antimicrobials by decreasing the intracellular concentration of drugs. This protective barrier consists of a series of transporter proteins, which are located in the bacterial cell membrane and periplasm and remove diverse extraneous substrates, including antimicrobials, organic solvents, toxic heavy metals, etc., from bacterial cells. This review systematically and comprehensively summarizes the functions of multiple efflux pumps families and discusses their potential applications. The biological functions of efflux pumps including their promotion of multidrug resistance, biofilm formation, quorum sensing, and survival and pathogenicity of bacteria are elucidated. The potential applications of efflux pump-related genes/proteins for the detection of antibiotic residues and antimicrobial resistance are also analyzed. Last but not least, efflux pump inhibitors, especially those of plant origin, are discussed. Full article
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