Research

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14 pages, 1053 KiB

Open AccessFeature PaperArticle

Thiostrepton: A Novel Therapeutic Drug Candidate for Mycobacterium abscessus Infection

by Tae Ho Kim, Bui Thi Bich Hanh, Guehye Kim, Da-Gyum Lee, June-Woo Park, So Eui Lee, Jae-Sung Kim, Byoung Soo Kim, Sungweon Ryoo, Eun-Kyeong Jo and Jichan Jang

Molecules 2019, 24(24), 4511; https://doi.org/10.3390/molecules24244511 - 10 Dec 2019

Cited by 21 | Viewed by 4068

Abstract

Mycobacterium abscessus is a rapid-growing, multidrug-resistant, non-tuberculous mycobacterial species responsible for a variety of human infections, such as cutaneous and pulmonary infections. M. abscessus infections are very difficult to eradicate due to the natural and acquired multidrug resistance profiles of M. abscessus. [...] Read more.

Mycobacterium abscessus is a rapid-growing, multidrug-resistant, non-tuberculous mycobacterial species responsible for a variety of human infections, such as cutaneous and pulmonary infections. M. abscessus infections are very difficult to eradicate due to the natural and acquired multidrug resistance profiles of M. abscessus. Thus, there is an urgent need for the development of effective drugs or regimens against M. abscessus infections. Here, we report the activity of a US Food and Drug Administration approved drug, thiostrepton, against M. abscessus. We found that thiostrepton significantly inhibited the growth of M. abscessus wild-type strains, subspecies, clinical isolates, and drug-resistant mutants in vitro and in macrophages. In addition, treatment of macrophages with thiostrepton significantly decreased proinflammatory cytokine production in a dose-dependent manner, suggesting an inhibitory effect of thiostrepton on inflammation induced during M. abscessus infection. We further showed that thiostrepton exhibits antimicrobial effects in vivo using a zebrafish model of M. abscessus infection. Full article

(This article belongs to the Special Issue Chemical Biology of Antimicrobial Resistance)

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20 pages, 5629 KiB

Open AccessArticle

Synthesis, Docking Studies, and In Vitro Evaluation of Some Novel Thienopyridines and Fused Thienopyridine–Quinolines as Antibacterial Agents and DNA Gyrase Inhibitors

by Eman M. Mohi El-Deen, Eman A. Abd El-Meguid, Sherifa Hasabelnaby, Eman A. Karam and Eman S. Nossier

Molecules 2019, 24(20), 3650; https://doi.org/10.3390/molecules24203650 - 10 Oct 2019

Cited by 43 | Viewed by 3131

Abstract

A series of novel thienopyridines and pyridothienoquinolines (3a,b–14) was synthesized, starting with 2-thioxo-1,2-dihydropyridine-3-carbonitriles 1a and 1b. All compounds were evaluated for their in vitro antimicrobial activity against six bacterial strains. Compounds 3a,b, 4a, 5b, 6a,b, 7a, 9b, 12b, and 14 [...] Read more.

A series of novel thienopyridines and pyridothienoquinolines (3a,b–14) was synthesized, starting with 2-thioxo-1,2-dihydropyridine-3-carbonitriles 1a and 1b. All compounds were evaluated for their in vitro antimicrobial activity against six bacterial strains. Compounds 3a,b, 4a, 5b, 6a,b, 7a, 9b, 12b, and 14 showed significant growth inhibition activity against both Gram-positive and Gram-negative bacteria compared with the reference drug. The most active compounds (4a, 7a, 9b, and 12b) against Staphylococcus aureus were also tested for their in vitro inhibitory action on methicillin-resistant Staphylococcus aureus (MRSA). The tested compounds showed promising inhibition activity, with the performance of 12b being equal to gentamicin and that of 7a exceeding it. Moreover, the most promising compounds were also screened for their Escherichia coli DNA gyrase inhibitory activity, compared with novobiocin as a reference DNA gyrase inhibitor. The results revealed that compounds (3a, 3b, 4a, 9b, and 12b) had the highest inhibitory capacity, with IC₅₀ values of 2.26–5.87 µM (that of novobiocin is equal to 4.17 µM). Docking studies were performed to identify the mode of binding of the tested compounds to the active site of E. coli DNA gyrase B. Full article

(This article belongs to the Special Issue Chemical Biology of Antimicrobial Resistance)

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14 pages, 1991 KiB

Open AccessArticle

Fusion of Lysostaphin to an Albumin Binding Domain Prolongs Its Half-Life and Bactericidal Activity in the Systemic Circulation

by Alexander V. Grishin, Nikita V. Shestak, Natalia V. Lavrova, Alexander M. Lyashchuk, Liubov I. Popova, Natalia V. Strukova, Maria S. Generalova, Anna V. Ryazanova, Nikita B. Polyakov, Zoya M. Galushkina, Lyubov A. Soboleva, Irina S. Boksha, Anna S. Karyagina and Vladimir G. Lunin

Molecules 2019, 24(16), 2892; https://doi.org/10.3390/molecules24162892 - 09 Aug 2019

Cited by 10 | Viewed by 3528

Abstract

Antibacterial lysins are promising proteins that are active against both antibiotic-susceptible and antibiotic-resistant bacterial strains. However, a major limitation of antibacterial lysins is their fast elimination from systemic circulation. PEGylation increases the plasma half-life of lysins but renders them inactive. Here we report [...] Read more.

Antibacterial lysins are promising proteins that are active against both antibiotic-susceptible and antibiotic-resistant bacterial strains. However, a major limitation of antibacterial lysins is their fast elimination from systemic circulation. PEGylation increases the plasma half-life of lysins but renders them inactive. Here we report the construction of a fusion protein of lysostaphin, a potent anti-staphylococcal lysin, and an albumin-binding domain from streptococcal protein G. The resulting fusion protein was less active than the parent enzyme lysostaphin, but it still retained significant antibacterial activity even when bound to serum albumin. The terminal half-life of the fusion protein in rats was five-fold greater than that of lysostaphin (7.4 vs. 1.5 h), and the area under the curve increased more than 115 times. Most importantly, this increase in systemic circulation time compensated for the decrease in activity. The plasma from rats that received an injection of the fusion protein retained bactericidal activity for up to 7 h, while plasma from rats that received plain lysostaphin lacked any detectable activity after 4 h. To the best of our knowledge, this is the first report of an antibacterial lysin with both improved pharmacokinetic parameters and prolonged bactericidal activity in the systemic circulation. Full article

(This article belongs to the Special Issue Chemical Biology of Antimicrobial Resistance)

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14 pages, 3926 KiB

Open AccessArticle

An Eco-Friendly Technique: Solvent-Free Microwave Synthesis and Docking Studies of Some New Pyridine Nucleosides and Their Pharmacological Significance

by Majed Alrobaian, Sana Al Azwari, Amany Belal and Hany A. Eldeab

Molecules 2019, 24(10), 1969; https://doi.org/10.3390/molecules24101969 - 22 May 2019

Cited by 8 | Viewed by 2505

Abstract

Two series of novel 5-arylazo-3-cyano-2-(2″,3″,4″,6″-tetra-O-acetyl-β-d-galacto pyranosyloxy) pyridines and 3-cyano-2-(2″,3″,4″,6″-tetra-O-acetyl-β-d-galactopyranosyloxy) pyridines were synthesized in high yields utilizing a microwave-assisted synthesis tool guided by the principles of green chemistry. The chemical structures of the new substances were [...] Read more.

Two series of novel 5-arylazo-3-cyano-2-(2″,3″,4″,6″-tetra-O-acetyl-β-d-galacto pyranosyloxy) pyridines and 3-cyano-2-(2″,3″,4″,6″-tetra-O-acetyl-β-d-galactopyranosyloxy) pyridines were synthesized in high yields utilizing a microwave-assisted synthesis tool guided by the principles of green chemistry. The chemical structures of the new substances were confirmed on the basis of their elemental analysis and spectroscopic data (FT-IR, 1D, 2D-NMR). Activity against different bacterial strains was studied. The anticancer potential of the new compounds is also discussed. Molecular docking was used as a tool in this research work to get better insight into the possible interactions, affinities, and expected modes of binding of the most promising derivatives of the potential chemotherapeutic target (DHFR). Full article

(This article belongs to the Special Issue Chemical Biology of Antimicrobial Resistance)

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13 pages, 1801 KiB

Open AccessArticle

The Influence of Dimerization on the Pharmacokinetics and Activity of an Antibacterial Enzyme Lysostaphin

by Alexander V. Grishin, Natalia V. Lavrova, Alexander M. Lyashchuk, Natalia V. Strukova, Maria S. Generalova, Anna V. Ryazanova, Nikita V. Shestak, Irina S. Boksha, Nikita B. Polyakov, Zoya M. Galushkina, Lyubov A. Soboleva, Sergey S. Vetchinin, Vitaliy M. Pavlov, Anna S. Karyagina and Vladimir G. Lunin

Molecules 2019, 24(10), 1879; https://doi.org/10.3390/molecules24101879 - 16 May 2019

Cited by 13 | Viewed by 3238

Abstract

The increasing prevalence of antibiotic-resistant strains of pathogenic bacteria is a major healthcare problem. Antibacterial lysins are enzymes that cleave the peptidoglycan of the bacterial cell wall. These proteins hold potential as a supplement or an alternative to traditional antibiotics since they are [...] Read more.

The increasing prevalence of antibiotic-resistant strains of pathogenic bacteria is a major healthcare problem. Antibacterial lysins are enzymes that cleave the peptidoglycan of the bacterial cell wall. These proteins hold potential as a supplement or an alternative to traditional antibiotics since they are active against antibiotic resistant strains. However, antibacterial lysins are rapidly eliminated from the systemic circulation, which limits their application. Dimerization of an anti-pneumococcal lysin Cpl-1 has been demonstrated to decrease the clearance rate of this protein in mice. In the present work, we constructed a dimer of an anti-staphylococcal lysin lysostaphin by fusing it with an anti-parallel α-helical dimerization domain. Lysostaphin dimer had a more favorable pharmacokinetic profile with increased terminal half-life and area under the curve (AUC) values compared to monomeric lysostaphin. However, the staphylolytic activity of dimerized lysostaphin was decreased. This decrease in activity was likely caused by the dimerization; since the catalytic efficacy of lysostaphin dimer towards pentaglycine peptide was unaltered. Our results demonstrate that, although dimerization is indeed beneficial for the pharmacokinetics of antibacterial lysins, this approach might not be suitable for all lysins, as it can negatively affect the lysin activity. Full article

(This article belongs to the Special Issue Chemical Biology of Antimicrobial Resistance)

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12 pages, 3752 KiB

Open AccessArticle

Biofilm Formation in Acinetobacter Baumannii: Genotype-Phenotype Correlation

by Cheng-Hong Yang, Pai-Wei Su, Sin-Hua Moi and Li-Yeh Chuang

Molecules 2019, 24(10), 1849; https://doi.org/10.3390/molecules24101849 - 14 May 2019

Cited by 123 | Viewed by 9155

Abstract

Strains of Acinetobacter baumannii are commensal and opportunistic pathogens that have emerged as problematic hospital pathogens due to its biofilm formation ability and multiple antibiotic resistances. The biofilm-associated pathogens usually exhibit dramatically decreased susceptibility to antibiotics. This study was aimed to investigate the [...] Read more.

Strains of Acinetobacter baumannii are commensal and opportunistic pathogens that have emerged as problematic hospital pathogens due to its biofilm formation ability and multiple antibiotic resistances. The biofilm-associated pathogens usually exhibit dramatically decreased susceptibility to antibiotics. This study was aimed to investigate the correlation of biofilm-forming ability, antibiotic resistance and biofilm-related genes of 154 A. baumannii isolates which were collected from a teaching hospital in Taiwan. Biofilm-forming ability of the isolates was evaluated by crystal violet staining and observed by scanning electron microscopy. Antibiotic susceptibility was determined by disc diffusion method and minimum inhibitory concentration; the biofilm-related genes were screened by polymerase chain reaction. Results showed that among the 154 tested isolates, 15.6% of the clinical isolates were weak biofilm producers, while 32.5% and 45.4% of them possessed moderate and strong biofilm formation ability, respectively. The experimental results revealed that the multiple drug resistant isolates usually provided a higher biofilm formation. The prevalence of biofilm related genes including bap, bla_PER-1, csuE and ompA among the isolated strains was 79.2%, 38.3%, 91.6%, and 68.8%, respectively. The results indicated that the antibiotic resistance, the formation of biofilm and the related genes were significantly correlated. The results of this study can effectively help to understand the antibiotic resistant mechanism and provides the valuable information to the screening, identification, diagnosis, treatment and control of clinical antibiotic-resistant pathogens. Full article

(This article belongs to the Special Issue Chemical Biology of Antimicrobial Resistance)

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11 pages, 5346 KiB

Open AccessArticle

Structural Basis for the Inhibition of the Autophosphorylation Activity of HK853 by Luteolin

by Yuan Zhou, Liqun Huang, Shixia Ji, Shi Hou, Liang Luo, Conggang Li, Maili Liu, Yixiang Liu and Ling Jiang

Molecules 2019, 24(5), 933; https://doi.org/10.3390/molecules24050933 - 07 Mar 2019

Cited by 10 | Viewed by 3079

Abstract

The two-component system (TCS) is a significant signal transduction system for bacteria to adapt to complicated and variable environments, and thus has recently been regarded as a novel target for developing antibacterial agents. The natural product luteolin (Lut) can inhibit the autophosphorylation activity [...] Read more.

The two-component system (TCS) is a significant signal transduction system for bacteria to adapt to complicated and variable environments, and thus has recently been regarded as a novel target for developing antibacterial agents. The natural product luteolin (Lut) can inhibit the autophosphorylation activity of the typical histidine kinase (HK) HK853 from Thermotoga maritime, but the inhibition mechanism is not known. Herein, we report on the binding mechanism of a typical flavone with HK853 by using solution NMR spectroscopy, isothermal titration calorimetry (ITC), and molecular docking. We show that luteolin inhibits the activity of HK853 by occupying the binding pocket of adenosine diphosphate (ADP) through hydrogen bonds and π-π stacking interaction structurally. Our results reveal a detailed mechanism for the inhibition of flavones and observe the conformational and dynamics changes of HK. These results should provide a feasible approach for antibacterial agent design from the view of the histidine kinases. Full article

(This article belongs to the Special Issue Chemical Biology of Antimicrobial Resistance)

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12 pages, 1531 KiB

Open AccessCommunication

Proof of an Outer Membrane Target of the Efflux Inhibitor Phe-Arg-β-Naphthylamide from Random Mutagenesis

by Sabine Schuster, Jürgen A. Bohnert, Martina Vavra, John W. Rossen and Winfried V. Kern

Molecules 2019, 24(3), 470; https://doi.org/10.3390/molecules24030470 - 29 Jan 2019

Cited by 19 | Viewed by 4030

Abstract

Phe-Arg-β-naphthylamide (PAβN) has been characterized as an efflux pump inhibitor (EPI) acting on the major multidrug resistance efflux transporters of Gram-negative bacteria, such as AcrB in Eschericha coli. In the present study, in vitro random mutagenesis was used to evolve resistance to [...] Read more.

Phe-Arg-β-naphthylamide (PAβN) has been characterized as an efflux pump inhibitor (EPI) acting on the major multidrug resistance efflux transporters of Gram-negative bacteria, such as AcrB in Eschericha coli. In the present study, in vitro random mutagenesis was used to evolve resistance to the sensitizing activity of PAβN with the aim of elucidating its mechanism of action. A strain was obtained that was phenotypically similar to a previously reported mutant from a serial selection approach that had no efflux-associated mutations. We could confirm that acrB mutations in the new mutant were unrelated to PAβN resistance. The next-generation sequencing of the two mutants revealed loss-of-function mutations in lpxM. An engineered lpxM knockout strain showed up to 16-fold decreased PAβN activity with large lipophilic drugs, while its efflux capacity, as well as the efficacy of other EPIs, remained unchanged. LpxM is responsible for the last acylation step in lipopolysaccharide (LPS) synthesis, and lpxM deficiency has been shown to result in penta-acylated instead of hexa-acylated lipid A. Modeling the two lipid A types revealed steric conformational changes due to underacylation. The findings provide evidence of a target site of PAβN in the LPS layer, and prove membrane activity contributing to its drug-sensitizing potency. Full article

(This article belongs to the Special Issue Chemical Biology of Antimicrobial Resistance)

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Review

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16 pages, 579 KiB

Open AccessReview

The Concept of an Ideal Antibiotic: Implications for Drug Design

by Márió Gajdács

Molecules 2019, 24(5), 892; https://doi.org/10.3390/molecules24050892 - 03 Mar 2019

Cited by 200 | Viewed by 12164

Abstract

The emergence and spread of antibiotic-resistant pathogens is a major public health issue, which requires global action of an intersectoral nature. Multidrug-resistant (MDR) pathogens—especially “ESKAPE” bacteria—can withstand lethal doses of antibiotics with various chemical structures and mechanisms of action. Pharmaceutical companies are increasingly [...] Read more.

The emergence and spread of antibiotic-resistant pathogens is a major public health issue, which requires global action of an intersectoral nature. Multidrug-resistant (MDR) pathogens—especially “ESKAPE” bacteria—can withstand lethal doses of antibiotics with various chemical structures and mechanisms of action. Pharmaceutical companies are increasingly turning away from participating in the development of new antibiotics, due to the regulatory environment and the financial risks. There is an urgent need for innovation in antibiotic research, as classical discovery platforms (e.g., mining soil Streptomycetes) are no longer viable options. In addition to discovery platforms, a concept of an ideal antibiotic should be postulated, to act as a blueprint for future drugs, and to aid researchers, pharmaceutical companies, and relevant stakeholders in selecting lead compounds. Based on 150 references, the aim of this review is to summarize current advances regarding the challenges of antibiotic drug discovery and the specific attributes of an ideal antibacterial drug (a prodrug or generally reactive compound with no specific target, broad-spectrum antibacterial activity, adequate penetration through the Gram-negative cell wall, activity in biofilms and in hard-to-treat infections, accumulation in macrophages, availability for oral administration, and for use in sensitive patient groups). Full article

(This article belongs to the Special Issue Chemical Biology of Antimicrobial Resistance)

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