Antibiotics

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4 pages, 168 KiB

Open AccessEditorial

Novel Targets and Mechanisms in Antimicrobial Drug Discovery

by Donatella Tondi

Antibiotics 2021, 10(2), 141; https://doi.org/10.3390/antibiotics10020141 - 1 Feb 2021

Cited by 6 | Viewed by 2098

Abstract

The spread of infections resistant to available anti-infective drugs is a serious menace to human health [...] Full article

(This article belongs to the Special Issue Novel Targets and Mechanisms in Antimicrobial Drug Discovery)

Research

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10 pages, 2340 KiB

Open AccessArticle

Anticapsular and Antifungal Activity of α-Cyperone

by Connor Horn and Govindsamy Vediyappan

Antibiotics 2021, 10(1), 51; https://doi.org/10.3390/antibiotics10010051 - 6 Jan 2021

Cited by 16 | Viewed by 2949

Abstract

Fungal infections affect 300 million people and cause 1.5 million deaths globally per year. With the number of immunosuppressed patients increasing steadily, there is an increasing number of patients infected with opportunistic fungal infections such as infections caused by the species of Candida [...] Read more.

Fungal infections affect 300 million people and cause 1.5 million deaths globally per year. With the number of immunosuppressed patients increasing steadily, there is an increasing number of patients infected with opportunistic fungal infections such as infections caused by the species of Candida and Cryptococcus. In fact, the drug-resistant Can. krusei and the emerging pan-antifungal resistant Can. auris pose a serious threat to human health as the existing limited antifungals are futile. To further complicate therapy, fungi produce capsules and spores that are resistant to most antifungal drugs/host defenses. Novel antifungal drugs are urgently needed to fill unmet medical needs. From screening a collection of medicinal plant sources for antifungal activity, we have identified an active fraction from the rhizome of Cyperus rotundus, the nut grass plant. The fraction contained α-Cyperone, an essential oil that showed fungicidal activity against different species of Candida. Interestingly, the minimal inhibitory concentration of α-Cyperone was reduced 8-fold when combined with a clinical antifungal drug, fluconazole, indicating its antifungal synergistic potential and could be useful for combination therapy. Furthermore, α-Cyperone affected the synthesis of the capsule in Cryp. neoformans, a causative agent of fungal meningitis in humans. Further work on mechanistic understanding of α-Cyperone against fungal virulence could help develop a novel antifungal agent for drug-resistant fungal pathogens. Full article

(This article belongs to the Special Issue Novel Targets and Mechanisms in Antimicrobial Drug Discovery)

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13 pages, 4397 KiB

Open AccessCommunication

A New Promising Anti-Infective Agent Inhibits Biofilm Growth by Targeting Simultaneously a Conserved RNA Function That Controls Multiple Genes

by Thorsten M. Seyler, Christina Moore, Haein Kim, Sheetal Ramachandran and Paul F. Agris

Antibiotics 2021, 10(1), 41; https://doi.org/10.3390/antibiotics10010041 - 4 Jan 2021

Cited by 6 | Viewed by 2826

Abstract

Combating single and multi-drug-resistant infections in the form of biofilms is an immediate challenge. The challenge is to discover innovative targets and develop novel chemistries that combat biofilms and drug-resistant organisms, and thwart emergence of future resistant strains. An ideal novel target would [...] Read more.

Combating single and multi-drug-resistant infections in the form of biofilms is an immediate challenge. The challenge is to discover innovative targets and develop novel chemistries that combat biofilms and drug-resistant organisms, and thwart emergence of future resistant strains. An ideal novel target would control multiple genes, and can be inhibited by a single compound. We previously demonstrated success against Staphylococcus aureus biofilms by targeting the tRNA-dependent regulated T-box genes, not present in the human host. Present in Gram-positive bacteria, T-box genes attenuate transcription with a riboswitch-like element that regulates the expression of aminoacyl-tRNA synthetases and amino acid metabolism genes required for cell viability. PKZ18, the parent of a family of compounds selected in silico from 305,000 molecules, inhibits the function of the conserved T-box regulatory element and thus blocks growth of antibiotic-resistant S. aureus in biofilms. The PKZ18 analog PKZ18-22 was 10-fold more potent than vancomycin in inhibiting growth of S. aureus in biofilms. In addition, PKZ18-22 has a synergistic effect with existing antibiotics, e.g., gentamicin and rifampin. PKZ18-22 inhibits the T-box regulatory mechanism, halts the transcription of vital genes, and results in cell death. These effects are independent of the growth state, planktonic or biofilm, of the bacteria, and could inhibit emergent strains. Full article

(This article belongs to the Special Issue Novel Targets and Mechanisms in Antimicrobial Drug Discovery)

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18 pages, 977 KiB

Open AccessArticle

Amidochelocardin Overcomes Resistance Mechanisms Exerted on Tetracyclines and Natural Chelocardin

by Fabienne Hennessen, Marcus Miethke, Nestor Zaburannyi, Maria Loose, Tadeja Lukežič, Steffen Bernecker, Stephan Hüttel, Rolf Jansen, Judith Schmiedel, Moritz Fritzenwanker, Can Imirzalioglu, Jörg Vogel, Alexander J. Westermann, Thomas Hesterkamp, Marc Stadler, Florian Wagenlehner, Hrvoje Petković, Jennifer Herrmann and Rolf Müller

Antibiotics 2020, 9(9), 619; https://doi.org/10.3390/antibiotics9090619 - 18 Sep 2020

Cited by 11 | Viewed by 4857

Abstract

The reassessment of known but neglected natural compounds is a vital strategy for providing novel lead structures urgently needed to overcome antimicrobial resistance. Scaffolds with resistance-breaking properties represent the most promising candidates for a successful translation into future therapeutics. Our study focuses on [...] Read more.

The reassessment of known but neglected natural compounds is a vital strategy for providing novel lead structures urgently needed to overcome antimicrobial resistance. Scaffolds with resistance-breaking properties represent the most promising candidates for a successful translation into future therapeutics. Our study focuses on chelocardin, a member of the atypical tetracyclines, and its bioengineered derivative amidochelocardin, both showing broad-spectrum antibacterial activity within the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) panel. Further lead development of chelocardins requires extensive biological and chemical profiling to achieve favorable pharmaceutical properties and efficacy. This study shows that both molecules possess resistance-breaking properties enabling the escape from most common tetracycline resistance mechanisms. Further, we show that these compounds are potent candidates for treatment of urinary tract infections due to their in vitro activity against a large panel of multidrug-resistant uropathogenic clinical isolates. In addition, the mechanism of resistance to natural chelocardin was identified as relying on efflux processes, both in the chelocardin producer Amycolatopsis sulphurea and in the pathogen Klebsiella pneumoniae. Resistance development in Klebsiella led primarily to mutations in ramR, causing increased expression of the acrAB-tolC efflux pump. Most importantly, amidochelocardin overcomes this resistance mechanism, revealing not only the improved activity profile but also superior resistance-breaking properties of this novel antibacterial compound. Full article

(This article belongs to the Special Issue Novel Targets and Mechanisms in Antimicrobial Drug Discovery)

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17 pages, 1146 KiB

Open AccessArticle

Synthesis, ADMET Properties, and In Vitro Antimicrobial and Antibiofilm Activity of 5-Nitro-2-thiophenecarbaldehyde N-((E)-(5-Nitrothienyl)methylidene)hydrazone (KTU-286) against Staphylococcus aureus with Defined Resistance Mechanisms

by Povilas Kavaliauskas, Birute Grybaite, Vytautas Mickevicius, Ruta Petraitiene, Ramune Grigaleviciute, Rita Planciuniene, Philip Gialanella, Alius Pockevicius and Vidmantas Petraitis

Antibiotics 2020, 9(9), 612; https://doi.org/10.3390/antibiotics9090612 - 17 Sep 2020

Cited by 25 | Viewed by 3463

Abstract

The emergence of drug-resistant Staphylococcus aureus is responsible for high morbidity and mortality worldwide. New therapeutic options are needed to fight the increasing antimicrobial resistance among S. aureus in the clinical setting. We, therefore, characterized the in silico absorption, distribution, metabolism, elimination, and [...] Read more.

The emergence of drug-resistant Staphylococcus aureus is responsible for high morbidity and mortality worldwide. New therapeutic options are needed to fight the increasing antimicrobial resistance among S. aureus in the clinical setting. We, therefore, characterized the in silico absorption, distribution, metabolism, elimination, and toxicity (ADMET) and in vitro antimicrobial activity of 5-nitro-2-thiophenecarbaldehyde N-((E)-(5-nitrothienyl)methylidene)hydrazone (KTU-286) against drug-resistant S. aureus strains with genetically defined resistance mechanisms. The antimicrobial activity of KTU-286 was determined by CLSI recommendations. The ADMET properties were estimated by using in silico modeling. The activity on biofilm integrity was examined by crystal violet assay. KTU-286 demonstrated low estimated toxicity and low skin permeability. The highest antimicrobial activity was observed among pan-susceptible (Pan-S) S. aureus (minimal inhibitory concentration (MIC) 0.5–2.0 µg/mL, IC₅₀ = 0.460 µg/mL), followed by vancomycin resistant S. aureus (VRSA) (MIC 4.0 µg/mL, IC₅₀ = 1.697 µg/mL) and methicillin-resistant S. aureus (MRSA) (MIC 1.0–16.0 µg/mL, IC₅₀ = 2.282 µg/mL). KTU-286 resulted in significant (p < 0.05) loss of S. aureus biofilm integrity in vitro. Further studies are needed for a better understanding of safety, synergistic relationship, and therapeutic potency of KTU-286. Full article

(This article belongs to the Special Issue Novel Targets and Mechanisms in Antimicrobial Drug Discovery)

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15 pages, 5979 KiB

Open AccessArticle

Indoline-6-Sulfonamide Inhibitors of the Bacterial Enzyme DapE

by Cory T. Reidl, Tahirah K. Heath, Iman Darwish, Rachel M. Torrez, Maxwell Moore, Elliot Gild, Boguslaw P. Nocek, Anna Starus, Richard C. Holz and Daniel P. Becker

Antibiotics 2020, 9(9), 595; https://doi.org/10.3390/antibiotics9090595 - 11 Sep 2020

Cited by 11 | Viewed by 3952

Abstract

Inhibitors of the bacterial enzyme dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE; EC 3.5.1.18) hold promise as antibiotics with a new mechanism of action. Herein we describe the discovery of a new series of indoline sulfonamide DapE inhibitors from a high-throughput screen [...] Read more.

Inhibitors of the bacterial enzyme dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE; EC 3.5.1.18) hold promise as antibiotics with a new mechanism of action. Herein we describe the discovery of a new series of indoline sulfonamide DapE inhibitors from a high-throughput screen and the synthesis of a series of analogs. Inhibitory potency was measured by a ninhydrin-based DapE assay recently developed by our group. Molecular docking experiments suggest active site binding with the sulfonamide acting as a zinc-binding group (ZBG). Full article

(This article belongs to the Special Issue Novel Targets and Mechanisms in Antimicrobial Drug Discovery)

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16 pages, 3108 KiB

Open AccessArticle

Anti-Tubercular Properties of 4-Amino-5-(4-Fluoro-3- Phenoxyphenyl)-4H-1,2,4-Triazole-3-Thiol and Its Schiff Bases: Computational Input and Molecular Dynamics

by Katharigatta N. Venugopala, Mahmoud Kandeel, Melendhran Pillay, Pran Kishore Deb, Hassan H. Abdallah, Mohamad Fawzi Mahomoodally and Deepak Chopra

Antibiotics 2020, 9(9), 559; https://doi.org/10.3390/antibiotics9090559 - 31 Aug 2020

Cited by 33 | Viewed by 4496

Abstract

In the present investigation, the parent compound 4-amino-5-(4-fluoro-3-phenoxyphenyl)-4H-1,2,4-triazole-3-thiol (1) and its Schiff bases 2, 3, and 4 were subjected to whole-cell anti-TB against H37Rv and multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) by resazurin microtiter assay (REMA) [...] Read more.

In the present investigation, the parent compound 4-amino-5-(4-fluoro-3-phenoxyphenyl)-4H-1,2,4-triazole-3-thiol (1) and its Schiff bases 2, 3, and 4 were subjected to whole-cell anti-TB against H37Rv and multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) by resazurin microtiter assay (REMA) plate method. Test compound 1 exhibited promising anti-TB activity against H37Rv and MDR strains of MTB at 5.5 µg/mL and 11 µg/mL, respectively. An attempt to identify the suitable molecular target for compound 1 was performed using a set of triazole thiol cellular targets, including β-ketoacyl carrier protein synthase III (FABH), β-ketoacyl ACP synthase I (KasA), CYP121, dihydrofolate reductase, enoyl-acyl carrier protein reductase, and N-acetylglucosamine-1-phosphate uridyltransferase. MTB β-ketoacyl ACP synthase I (KasA) was identified as the cellular target for the promising anti-TB parent compound 1 via docking and molecular dynamics simulation. MM(GB/PB)SA binding free energy calculation revealed stronger binding of compound 1 compared with KasA standard inhibitor thiolactomycin (TLM). The inhibitory mechanism of test compound 1 involves the formation of hydrogen bonding with the catalytic histidine residues, and it also impedes access of fatty-acid substrates to the active site through interference with α5–α6 helix movement. Test compound 1-specific structural changes at the ALA274–ALA281 loop might be the contributing factor underlying the stronger anti-TB effect of compound 1 when compared with TLM, as it tends to adopt a closed conformation for the access of malonyl substrate to its binding site. Full article

(This article belongs to the Special Issue Novel Targets and Mechanisms in Antimicrobial Drug Discovery)

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12 pages, 1715 KiB

Open AccessArticle

Ceftazidime-Avibactam Combination Therapy Compared to Ceftazidime-Avibactam Monotherapy for the Treatment of Severe Infections Due to Carbapenem-Resistant Pathogens: A Systematic Review and Network Meta-Analysis

by Marco Fiore, Aniello Alfieri, Sveva Di Franco, Maria Caterina Pace, Vittorio Simeon, Giulia Ingoglia and Andrea Cortegiani

Antibiotics 2020, 9(7), 388; https://doi.org/10.3390/antibiotics9070388 - 7 Jul 2020

Cited by 56 | Viewed by 7083

Abstract

Ceftazidime-avibactam (CZA) is a novel beta-lactam beta-lactamase inhibitor combination approved for the treatment of complicated urinary tract infections, complicated intra-abdominal infections, and for hospital-acquired/ventilator-associated pneumonia. The aim of this systematic review (PROSPERO registration number: CRD42019128927) was to evaluate the effectiveness of CZA combination [...] Read more.

Ceftazidime-avibactam (CZA) is a novel beta-lactam beta-lactamase inhibitor combination approved for the treatment of complicated urinary tract infections, complicated intra-abdominal infections, and for hospital-acquired/ventilator-associated pneumonia. The aim of this systematic review (PROSPERO registration number: CRD42019128927) was to evaluate the effectiveness of CZA combination therapy versus CZA monotherapy in the treatment of severe infections. The databases included in the search, until 12 February 2020, were MEDLINE by PubMed, EMBASE, and The Cochrane Central Register of Controlled Trials. We included both randomized controlled trials (RCTs) and non-randomized studies published in peer-reviewed journals and in the English language. The primary outcome was all-cause mortality (longest follow-up) evaluated in patients with the diagnosis of infection with at least one pathogen; secondary outcomes were clinical and microbiological improvement/cure. Thirteen studies were included in the qualitative synthesis: 7 RCTs and 6 retrospective studies All the six retrospective studies identified carbapenamase-producing Enterobacteriaceae (CRE) as the cause of infection and for this reason were included in the network meta-analysis (NMA); the quality of the studies, assessed using the New Castle-Ottawa Scale, was moderate-high. In all the six retrospective studies included in the NMA, CZA was used in large part for off-label indications (mostly blood stream infections: 80–100% of patients included). No difference in mortality rate was observed in patients undergoing CZA combination therapy compared to CZA monotherapy [n = 503 patients, direct evidence OR: 0.96, 95% CI: 0.65–1.41]. Full article

(This article belongs to the Special Issue Novel Targets and Mechanisms in Antimicrobial Drug Discovery)

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12 pages, 2904 KiB

Open AccessArticle

New Insights into Bioactive Compounds from the Medicinal Plant Spathodea campanulata P. Beauv. and Their Activity against Helicobacter pylori

by Corinne Raïssa Ngnameko, Lucia Marchetti, Barbara Zambelli, Antonio Quotadamo, Davide Roncarati, Davide Bertelli, Frederic Nico Njayou, Stella I. Smith, Paul F. Moundipa, Maria Paola Costi and Federica Pellati

Antibiotics 2020, 9(5), 258; https://doi.org/10.3390/antibiotics9050258 - 15 May 2020

Cited by 4 | Viewed by 4191

Abstract

The medicinal plant Spathodea campanulata P. Beauv. (Bignoniaceae) has been traditionally applied for the prevention and treatment of diseases of the kidney and urinary system, the skin, the gastrointestinal tract, and inflammation in general. The present work shows for the first time how [...] Read more.

The medicinal plant Spathodea campanulata P. Beauv. (Bignoniaceae) has been traditionally applied for the prevention and treatment of diseases of the kidney and urinary system, the skin, the gastrointestinal tract, and inflammation in general. The present work shows for the first time how chemical components from this plant inhibit Helicobacter pylori growth by urease inhibition and modulation of virulence factors. The crude extract and the main fractions of S. campanulata bark were tested on H. pylori isolated strains and the active ones were further fractionated. Fractions and sub-fractions of the plant crude extract were characterized by ultra-high-performance liquid chromatographic tandem high resolution-mass spectrometry detection (UHPLC-HRMS). Several phenolics and triterpenoids were identified. Among the sub-fractions obtained, SB2 showed the capacity to inhibit H. pylori urease in a heterologous bacterial model. One additional sub-fraction (SE3) was able to simultaneously modulate the expression of two adhesins (HopZ and BabA) and one cytotoxin (CagA). The flavonol kaempferol was identified as the most interesting compound that deserves further investigation as a new hit for its capacity to modulate H. pylori virulence factors. Full article

(This article belongs to the Special Issue Novel Targets and Mechanisms in Antimicrobial Drug Discovery)

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Review

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22 pages, 3924 KiB

Open AccessEditor’s ChoiceReview

Riboswitches as Drug Targets for Antibiotics

by Vipul Panchal and Ruth Brenk

Antibiotics 2021, 10(1), 45; https://doi.org/10.3390/antibiotics10010045 - 5 Jan 2021

Cited by 62 | Viewed by 8804

Abstract

Riboswitches reside in the untranslated region of RNA and regulate genes involved in the biosynthesis of essential metabolites through binding of small molecules. Since their discovery at the beginning of this century, riboswitches have been regarded as potential antibacterial targets. Using fragment screening, [...] Read more.

Riboswitches reside in the untranslated region of RNA and regulate genes involved in the biosynthesis of essential metabolites through binding of small molecules. Since their discovery at the beginning of this century, riboswitches have been regarded as potential antibacterial targets. Using fragment screening, high-throughput screening and rational ligand design guided by X-ray crystallography, lead compounds against various riboswitches have been identified. Here, we review the current status and suitability of the thiamine pyrophosphate (TPP), flavin mononucleotide (FMN), glmS, guanine, and other riboswitches as antibacterial targets and discuss them in a biological context. Further, we highlight challenges in riboswitch drug discovery and emphasis the need to develop riboswitch specific high-throughput screening methods. Full article

(This article belongs to the Special Issue Novel Targets and Mechanisms in Antimicrobial Drug Discovery)

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17 pages, 5475 KiB

Open AccessReview

Can We Exploit β-Lactamases Intrinsic Dynamics for Designing More Effective Inhibitors?

by Eleonora Gianquinto, Donatella Tondi, Giulia D'Arrigo, Loretta Lazzarato and Francesca Spyrakis

Antibiotics 2020, 9(11), 833; https://doi.org/10.3390/antibiotics9110833 - 21 Nov 2020

Cited by 6 | Viewed by 2998

Abstract

β-lactamases (BLs) represent the most frequent cause of antimicrobial resistance in Gram-negative bacteria. Despite the continuous efforts in the development of BL inhibitors (BLIs), new BLs able to hydrolyze the last developed antibiotics rapidly emerge. Moreover, the insurgence rate of effective mutations is [...] Read more.

β-lactamases (BLs) represent the most frequent cause of antimicrobial resistance in Gram-negative bacteria. Despite the continuous efforts in the development of BL inhibitors (BLIs), new BLs able to hydrolyze the last developed antibiotics rapidly emerge. Moreover, the insurgence rate of effective mutations is far higher than the release of BLIs able to counteract them. This results in a shortage of antibiotics that is menacing the effective treating of infectious diseases. The situation is made even worse by the co-expression in bacteria of BLs with different mechanisms and hydrolysis spectra, and by the lack of inhibitors able to hit them all. Differently from other targets, BL flexibility has not been deeply exploited for drug design, possibly because of the small protein size, for their apparent rigidity and their high fold conservation. In this mini-review, we discuss the evidence for BL binding site dynamics being crucial for catalytic efficiency, mutation effect, and for the design of new inhibitors. Then, we report on identified allosteric sites in BLs and on possible allosteric inhibitors, as a strategy to overcome the frequent occurrence of mutations in BLs and the difficulty of competing efficaciously with substrates. Nevertheless, allosteric inhibitors could work synergistically with traditional inhibitors, increasing the chances of restoring bacterial susceptibility towards available antibiotics. Full article

(This article belongs to the Special Issue Novel Targets and Mechanisms in Antimicrobial Drug Discovery)

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19 pages, 1771 KiB

Open AccessReview

Overcoming Intrinsic and Acquired Resistance Mechanisms Associated with the Cell Wall of Gram-Negative Bacteria

by Rachael E. Impey, Daniel A. Hawkins, J. Mark Sutton and Tatiana P. Soares da Costa

Antibiotics 2020, 9(9), 623; https://doi.org/10.3390/antibiotics9090623 - 19 Sep 2020

Cited by 57 | Viewed by 10532

Abstract

The global increase in multi-drug-resistant bacteria is severely impacting our ability to effectively treat common infections. For Gram-negative bacteria, their intrinsic and acquired resistance mechanisms are heightened by their unique cell wall structure. The cell wall, while being a target of some antibiotics, [...] Read more.

The global increase in multi-drug-resistant bacteria is severely impacting our ability to effectively treat common infections. For Gram-negative bacteria, their intrinsic and acquired resistance mechanisms are heightened by their unique cell wall structure. The cell wall, while being a target of some antibiotics, represents a barrier due to the inability of most antibacterial compounds to traverse and reach their intended target. This means that its composition and resulting mechanisms of resistance must be considered when developing new therapies. Here, we discuss potential antibiotic targets within the most well-characterised resistance mechanisms associated with the cell wall in Gram-negative bacteria, including the outer membrane structure, porins and efflux pumps. We also provide a timely update on the current progress of inhibitor development in these areas. Such compounds could represent new avenues for drug discovery as well as adjuvant therapy to help us overcome antibiotic resistance. Full article

(This article belongs to the Special Issue Novel Targets and Mechanisms in Antimicrobial Drug Discovery)

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