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Advances in Antibacterial Drug Discovery and Therapy

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (15 February 2019) | Viewed by 28889

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Special Issue Editor

Dr. Dianqing Sun

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Guest Editor

The Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, HI, USA
Interests: organic and medicinal chemistry; antibacterial and anticancer drug discovery

Special Issue Information

Dear Colleagues,

On behalf of the Journal of Clinical Medicine (JCM) editorial team, we are delighted to present a new Special Issue on the topic of “Advances in Antibacterial Drug Discovery and Therapy”, Guest Edited by Dr. Dianqing Sun, from the University of Hawaii at Hilo, USA.

Bacterial infections caused by Mycobacterium tuberculosis and other clinically significant pathogenic bacteria pose growing and serious threats to global public health. This problem is further compounded by mounting antibacterial drug resistance, limited antimicrobial therapy options, and the overall lack of new antibacterial development by the pharmaceutical industry. According to the Centers for Disease Control and Prevention (CDC), in the United States alone, there are more than two million illnesses and 23,000 deaths every year resulting from antibiotic-resistant bacterial infections, with added healthcare costs of about 20 billion dollars. In addition, a 2013 CDC report assigned Clostridium difficile (C. difficile), carbapenem-resistant Enterobacteriaceae, and drug-resistant Neisseria gonorrhoeae into the antibiotic resistance “urgent threat” category. C. difficile remains the most common cause of hospital-acquired diarrhea and can lead to a life-threatening infection or inflammation, particularly among the elderly. In the US, C. difficile is responsible for about 500,000 cases of infections and approximately 15,000 deaths each year, with added healthcare costs of one billion dollars. Notably, for drug resistant and more difficult-to-treat organisms including some gram-negative pathogens, older, more toxic, and costly last-resort antibiotics are increasingly being used to combat these serious infections. As a result, superbugs resistant to the last-resort antibiotics have also been on the rise. Therefore, there is a significant need to develop the next generation of safe antibiotics with improved efficacy and antibacterial resistance profiles.

This Special Issue highlights some recent and historical advances in antibacterial drug discovery and development. Topics may include, but are not limited to, natural product antibacterial drug discovery, small molecule antimicrobial agents, target identification and validation, hit to lead and lead optimization, structure-based design, combination antibiotic therapy, and clinical practice guidelines.

Dr. Dianqing Sun
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. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly 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 2600 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 drug discovery and development
antimicrobial resistance
medicinal chemistry
structure–activity relationship
chemical synthesis
rational design
computational modeling
natural product drug discovery
bacterial therapy
clinical practice

Published Papers (6 papers)

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Research

19 pages, 15054 KiB

Open AccessArticle

Indocyanine Green—Mediated Photodynamic Therapy Reduces Methicillin-Resistant Staphylococcus aureus Drug Resistance

by Tak-Wah Wong, Shu-Zhen Liao, Wen-Chien Ko, Chi-Jung Wu, Shin Bei Wu, Yin-Ching Chuang and I-Hsiu Huang

J. Clin. Med. 2019, 8(3), 411; https://doi.org/10.3390/jcm8030411 - 25 Mar 2019

Cited by 32 | Viewed by 5510

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) skin-wound infections are associated with considerable morbidity and mortality. Indocyanine green (ICG), a safe and inexpensive dye used in clinical imaging, can be activated by near-infrared in photodynamic therapy (PDT) and photothermal therapy (PTT) to effectively kill MRSA. However, how this treatment affects MRSA drug sensitivity remains unknown. The drug-sensitivity phenotypes, bacterial growth rate, and cell-wall thickness of three MRSA strains were analyzed after ICG-PDT. Drug-resistant gene expressions were determined by polymerase chain reaction (PCR) and quantitative reverse transcription (qRT)-PCR. Related protein expressions were examined with immunoblotting. Drug sensitivity was further evaluated in animal models. MRSA that survived the treatment grew faster, and the cell wall became thinner compared to parental cells. These cells became more sensitive to oxacillin, which was partly related to mecA complex gene deletion. Skin necrosis caused by ICG-PDT-treated MRSA infection was smaller and healed faster than that infected with parental cells. With oxacillin therapy, no bacteria could be isolated from mouse lung tissue infected with ICG-PDT-treated MRSA. ICG-PDT drives MRSA toward an oxacillin-sensitive phenotype. It has the potential to develop into an alternative or adjuvant clinical treatment against MRSA wound infections. Full article

(This article belongs to the Special Issue Advances in Antibacterial Drug Discovery and Therapy)

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14 pages, 18949 KiB

Open AccessArticle

A Personalized CYP2C19 Phenotype-Guided Dosing Regimen of Voriconazole Using a Population Pharmacokinetic Analysis

by Yun Kim, Su-jin Rhee, Wan Beom Park, Kyung-Sang Yu, In-Jin Jang and SeungHwan Lee

J. Clin. Med. 2019, 8(2), 227; https://doi.org/10.3390/jcm8020227 - 10 Feb 2019

Cited by 19 | Viewed by 4197

Abstract

Highly variable and non-linear pharmacokinetics of voriconazole are mainly caused by CYP2C19 polymorphisms. This study aimed to develop a mechanistic population pharmacokinetic model including the CYP2C19 phenotype, and to assess the appropriateness of various dosing regimens based on the therapeutic target. A total of 1,828 concentrations from 193 subjects were included in the population pharmacokinetic analysis. A three-compartment model with an inhibition compartment appropriately described the voriconazole pharmacokinetics reflecting auto-inhibition. Voriconazole clearance in the CYP2C19 intermediate metabolizers (IMs) and poor metabolizers (PMs) decreased by 17% and 53% compared to that in the extensive metabolizers (EMs). There was a time-dependent inhibition of clearance to 16.2% of its original value in the CYP2C19 EMs, and the extent of inhibition differed according to the CYP2C19 phenotypes. The proposed CYP2C19 phenotype-guided initial dosing regimens are 400 mg twice daily (bid) for EMs, 200 mg bid for IMs, and 100 mg bid for PMs. This CYP2C19 phenotype-guided initial dosing regimen will provide a rationale for individualizing the optimal voriconazole therapy. Full article

(This article belongs to the Special Issue Advances in Antibacterial Drug Discovery and Therapy)

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25 pages, 4254 KiB

Open AccessArticle

Discovery of Potential Plant-Derived Peptide Deformylase (PDF) Inhibitors for Multidrug-Resistant Bacteria Using Computational Studies

by Shailima Rampogu, Amir Zeb, Ayoung Baek, Chanin Park, Minky Son and Keun Woo Lee

J. Clin. Med. 2018, 7(12), 563; https://doi.org/10.3390/jcm7120563 - 17 Dec 2018

Cited by 20 | Viewed by 4667

Abstract

Bacterial peptide deformylase (PDF) is an attractive target for developing novel inhibitors against several types of multidrug-resistant bacteria. The objective of the current study is to retrieve potential phytochemicals as prospective drugs against Staphylococcus aureus peptide deformylase (SaPDF). The current study focuses on applying ligand-based pharmacophore model (PharmL) and receptor-based pharmacophore (PharmR) approaches. Utilizing 20 known active compounds, pharmL was built and validated using Fischer’s randomization, test set method and the decoy set method. PharmR was generated from the knowledge imparted by the Interaction Generation protocol implemented on the Discovery Studio (DS) v4.5 and was validated using the decoy set that was employed for pharmL. The selection of pharmR was performed based upon the selectivity score and further utilizing the Pharmacophore Comparison module available on the DS. Subsequently, the validated pharmacophore models were escalated for Taiwan Indigenous Plants (TIP) database screening and furthermore, a drug-like evaluation was performed. Molecular docking was initiated for the resultant compounds, employing CDOCKER (available on the DS) and GOLD. Eventually, the stability of the final PDF–hit complexes was affirmed using molecular dynamics (MD) simulation conducted by GROMACS v5.0.6. The redeemed hits demonstrated a similar binding mode and stable intermolecular interactions with the key residues, as determined by no aberrant behaviour for 30 ns. Taken together, it can be stated that the hits can act as putative scaffolds against SaPDF, with a higher therapeutic value. Furthermore, they can act as fundamental structures for designing new drug candidates. Full article

(This article belongs to the Special Issue Advances in Antibacterial Drug Discovery and Therapy)

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15 pages, 2783 KiB

Open AccessArticle

Effects of 462 nm Light-Emitting Diode on the Inactivation of Escherichia coli and a Multidrug-Resistant by Tetracycline Photoreaction

by Shiuh-Tsuen Huang, Chun-Yi Wu, Nan‐Yao Lee, Chien-Wei Cheng, Meei-Ju Yang, Yi-An Hung, Tak-Wah Wong and Ji-Yuan Liang

J. Clin. Med. 2018, 7(9), 278; https://doi.org/10.3390/jcm7090278 - 12 Sep 2018

Cited by 17 | Viewed by 4451

Abstract

The adaptability of bacterial resistance to antibiotics contributes to its high efficiency during evolution. Tetracycline (TC) is a broad-spectrum antimicrobial agent. Chromatographic analyses and mass spectrometry were used to study the effects of the light illumination of a 462 nm light-emitting diode (LED) on the conformational changes of TC in a phosphate buffer solution (PBS, pH 7.8). Especially, the inactivation of superoxide anion radicals (O₂•⁻) and Escherichia coli (E. coli), including that of a multidrug-resistant E. coli (MDR E. coli), were investigated during the photolysis of TC. A photolysis product of TC (PPT) was generated in an alkaline solution after the illumination of a blue light. The mass spectra of PPT had characteristic ion signals in m/z 459, 445, and 249.1 Da. The PPT has the molecular formula of C₂₂H₂₂N₂O₉, and the exact mass is 458.44 g/mol. The inactivation of MDR E. coli is not significant with TC treatment. The drug-resistant ability of MDR E. coli has a less significant effect on PPT, and the changed conformation of TC retained the inactivation ability of MDR E. coli upon blue light photoreaction. With TC, illuminated by a blue light in a pH 7.8 PBS, O₂•⁻ was generated from TC photolysis, which enhanced the inactivation of E. coli and MDR E. coli. A 96.6% inactivation rate of MDR E. coli was reached with TC under 2.0 mW/cm² blue light illumination at 25 ± 3 °C for 120 min, and the effects of the TC-treated photoreaction on MDR E. coli viability repressed the growth of MDR E. coli by 4 to 5 logs. The present study of the blue light photoreaction of TC offers a new approach to the inactivation of MDR E. coli. Full article

(This article belongs to the Special Issue Advances in Antibacterial Drug Discovery and Therapy)

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14 pages, 1391 KiB

Open AccessArticle

Antimycobacterial, Enzyme Inhibition, and Molecular Interaction Studies of Psoromic Acid in Mycobacterium tuberculosis: Efficacy and Safety Investigations

by Sherif T. S. Hassan, Miroslava Šudomová, Kateřina Berchová-Bímová, Shanmugaraj Gowrishankar and Kannan R. R. Rengasamy

J. Clin. Med. 2018, 7(8), 226; https://doi.org/10.3390/jcm7080226 - 20 Aug 2018

Cited by 11 | Viewed by 4483

Abstract

The current study explores the antimycobacterial efficacy of lichen-derived psoromic acid (PA) against clinical strains of Mycobacterium tuberculosis (M.tb). Additionally, the inhibitory efficacy of PA against two critical enzymes associated with M.tb, namely, UDP-galactopyranose mutase (UGM) and arylamine-N-acetyltransferase (TBNAT), as drug targets for antituberculosis therapy were determined. PA showed a profound inhibitory effect towards all the M.tb strains tested, with minimum inhibitory concentrations (MICs) ranging between 3.2 and 4.1 µM, and selectivity indices (SIs) ranging between 18.3 and 23.4. On the other hand, the standard drug isoniazid (INH) displayed comparably high MIC values (varying from 5.4 to 5.8 µM) as well as low SI values (13.0–13.9). Interestingly, PA did not exhibit any cytotoxic effects on a human liver hepatocellular carcinoma cell line even at the highest concentration tested (75 µM). PA demonstrated remarkable suppressing propensity against UGM compared to standard uridine-5'-diphosphate (UDP), with 85.8 and 99.3% of inhibition, respectively. In addition, PA also exerted phenomenal inhibitory efficacy (half maximal inhibitory concentration (IC₅₀) value = 8.7 µM, and 77.4% inhibition) against TBNAT compared with standard INH (IC₅₀ value = 6.2 µM and 96.3% inhibition). Furthermore, in silico analysis validated the outcomes of in vitro assays, as the molecular interactions of PA with the active sites of UGM and TBNAT were unveiled using molecular docking and structure–activity relationship studies. Concomitantly, our findings present PA as an effective and safe natural drug plausible for use in controlling tuberculosis infections. Full article

(This article belongs to the Special Issue Advances in Antibacterial Drug Discovery and Therapy)

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12 pages, 608 KiB

Open AccessArticle

Tobramycin-Linked Efflux Pump Inhibitor Conjugates Synergize Fluoroquinolones, Rifampicin and Fosfomycin against Multidrug-Resistant Pseudomonas aeruginosa

by Xuan Yang, Ronald Domalaon, Yinfeng Lyu, George G. Zhanel and Frank Schweizer

J. Clin. Med. 2018, 7(7), 158; https://doi.org/10.3390/jcm7070158 - 22 Jun 2018

Cited by 22 | Viewed by 4847

Abstract

In this study, we examined the in vitro effect of tobramycin-efflux pump inhibitor (TOB-EPI) conjugates in combinations with fluoroquinolones, rifampicin and fosfomycin on the growth of multi-drug resistant (MDR) and extremely-drug resistant (XDR) Pseudomonas aeruginosa. The TOB-EPI conjugates include tobramycin covalently linked to 1-(1-naphthylmethyl)-piperazine (NMP) (1), paroxetine (PAR) (2) and a dibasic peptide analogue of MC-04,124 (DBP) (3). Potent synergism was found for combinations of TOB-NMP (1), TOB-PAR (2) or TOB-DBP (3) with either fluoroquinolones (moxifloxacin, ciprofloxacin), rifampicin or fosfomycin against a panel of multidrug-resistant/extensively drug-resistant (MDR/XDR) P. aeruginosa clinical isolates. In the presence of ≤8 mg/L (6.1–7.2 µM) (≤¼ × MIC_adjuvant) concentration of the three conjugates, the MIC₈₀ of moxifloxacin, ciprofloxacin, rifampicin and fosfomycin were dramatically reduced. Furthermore, the MIC₈₀ of rifampicin (0.25–0.5 mg/L) and fosfomycin (8–16 mg/L) were reduced below their interpretative susceptibility breakpoints. Our data confirm the ability of TOB-NMP (1), TOB-PAR (2) and TOB-DBP (3) conjugates to strongly synergize with moxifloxacin, ciprofloxacin, rifampicin and fosfomycin against MDR/XDR P. aeruginosa. These synergistic combinations warrant further studies as there is an urgent need to develop new strategies to treat drug-resistant P. aeruginosa infections. Full article

(This article belongs to the Special Issue Advances in Antibacterial Drug Discovery and Therapy)

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