Antibiotics

Editorial

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2 pages, 430 KiB

Open AccessEditorial

Acknowledgement to Reviewers of Antibiotics in 2016

by Antibiotics Editorial Office

MDPI AG, St. Alban-Anlage 66, 4052 Basel, Switzerland

Antibiotics 2017, 6(1), 1; https://doi.org/10.3390/antibiotics6010001 - 10 Jan 2017

Viewed by 3616

Abstract

The editors of Antibiotics would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.[...] Full article

Research

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11 pages, 1283 KiB

Open AccessArticle

Fused-Ring Oxazolopyrrolopyridopyrimidine Systems with Gram-Negative Activity

by Yiyuan Chen, Jonathan G. Moloney, Kirsten E. Christensen

and Mark G. Moloney^*

Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK

Antibiotics 2017, 6(1), 2; https://doi.org/10.3390/antibiotics6010002 - 13 Jan 2017

Cited by 9 | Viewed by 5371

Abstract

Fused polyheterocyclic derivatives are available by annulation of a tetramate scaffold, and been shown to have antibacterial activity against a Gram-negative, but not a Gram-positive, bacterial strain. While the activity is not potent, these systems are structurally novel showing, in particular, a high [...] Read more.

Fused polyheterocyclic derivatives are available by annulation of a tetramate scaffold, and been shown to have antibacterial activity against a Gram-negative, but not a Gram-positive, bacterial strain. While the activity is not potent, these systems are structurally novel showing, in particular, a high level of polarity, and offer potential for the optimization of antibacterial activity. Full article

(This article belongs to the Special Issue Antibiotic Synthesis)

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11 pages, 3119 KiB

Open AccessArticle

Docking into Mycobacterium tuberculosis Thioredoxin Reductase Protein Yields Pyrazolone Lead Molecules for Methicillin-Resistant Staphylococcus aureus

by Noreena L. Sweeney¹, Lauren Lipker², Alicia M. Hanson¹

, Chris J. Bohl¹, Katie E. Engel², Kelsey S. Kalous³

, Mary E. Stemper⁴, Daniel S. Sem¹ and William R. Schwan^2,*

¹ Department of Pharmaceutical Sciences, Concordia University Wisconsin, 12800 N Lake Shore Dr, Mequon, WI 53097, USA

² Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA

³ Department of Biochemistry, Medical College of Wisconsin, Wauwatosa, WI 53226, USA

⁴ Marshfield Clinic Research Foundation, Marshfield, WI 54449, USA

Antibiotics 2017, 6(1), 4; https://doi.org/10.3390/antibiotics6010004 - 28 Jan 2017

Cited by 12 | Viewed by 6780

Abstract

The thioredoxin/thioredoxin reductase system (Trx/TrxR) is an attractive drug target because of its involvement in a number of important physiological processes, from DNA synthesis to regulating signal transduction. This study describes the finding of pyrazolone compounds that are active against Staphylococcus aureus. [...] Read more.

The thioredoxin/thioredoxin reductase system (Trx/TrxR) is an attractive drug target because of its involvement in a number of important physiological processes, from DNA synthesis to regulating signal transduction. This study describes the finding of pyrazolone compounds that are active against Staphylococcus aureus. Initially, the project was focused on discovering small molecules that may have antibacterial properties targeting the Mycobacterium tuberculosis thioredoxin reductase. This led to the discovery of a pyrazolone scaffold-containing compound series that showed bactericidal capability against S. aureus strains, including drug-resistant clinical isolates. The findings support continued development of the pyrazolone compounds as potential anti-S. aureus antibiotics. Full article

(This article belongs to the Special Issue Discover New Antibiotics 2016)

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9 pages, 519 KiB

Open AccessArticle

Moxifloxacin Increases Heart Rate in Humans

by Jay W. Mason^1,*

and Thomas E. Moon²

¹ Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA

² Tarizona eHealth Services, Tucson, AZ 85732, USA

Antibiotics 2017, 6(1), 5; https://doi.org/10.3390/antibiotics6010005 - 5 Feb 2017

Cited by 6 | Viewed by 5703

Abstract

(1) Background: We assessed the effect of moxifloxacin on heart rate, and reviewed the heart rate effects of other antibiotics; (2) Methods: A total of 335 normal volunteers had 12-lead electrocardiograms recorded at multiple time points before and during treatment with [...] Read more.

(1) Background: We assessed the effect of moxifloxacin on heart rate, and reviewed the heart rate effects of other antibiotics; (2) Methods: A total of 335 normal volunteers had 12-lead electrocardiograms recorded at multiple time points before and during treatment with moxifloxacin and with placebo in seven consecutive, thorough QT studies of crossover design; (3) Results: The average baseline heart rate across the seven studies was 61.5 bpm. The heart rate after moxifloxacin dosing was analyzed at five time points shared by all seven studies (hours 1, 2, 3, 12 and 24). The maximum mean heart rate (HR) increase for the seven studies combined was 2.4 bpm (95% CI 1.6, 3.3) at hour 2. The range of mean maximum increases among the seven studies was 2.1 to 4.3 bpm. For the seven studies combined, the increase was statistically significant at all but the 24 h time point. The maximum observed individual increase in HR was 36 bpm and the mean maximum increase was 30 ± 4.1 bpm by time point and 8 ± 6.9 bpm by subject. Many antibiotics increase HR, some several-fold more than moxifloxacin. However, clinicians and clinical investigators give little attention to this potential adverse effect in the medical literature; (4) Conclusions: The observed moxifloxacin-induced increase in HR is large enough to be clinically relevant, and it is a potentially important confounder in thorough QT studies using moxifloxacin as an active control. More attention to heart rate effects of antibiotics is warranted. Full article

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5 pages, 183 KiB

Open AccessCommunication

Diminished Antimicrobial Peptide and Antifungal Antibiotic Activities against Candida albicans in Denture Adhesive

by Amber M. Bates¹, Jorge L. Garaicoa², Carol L. Fischer³ and Kim A. Brogden^1,*

¹ Iowa Institute for Oral Health Research, College of Dentistry, The University of Iowa, Iowa City, IA 52242, USA

² Department of Restorative Dentistry, School of Dentistry, Oregon Health and Science University, Portland, OR 97201, USA

³ Department of Biology, Waldorf University, Forest City, IA 50436, USA

Antibiotics 2017, 6(1), 6; https://doi.org/10.3390/antibiotics6010006 - 6 Feb 2017

Cited by 8 | Viewed by 4730

Abstract

The underlying causes of denture stomatitis may be related to the long-term use of adhesives, which may predispose individuals to oral candidiasis. In this study, we hypothesize that antimicrobial peptides and antifungal antibiotics have diminished anti-Candida activities in denture adhesive. To show [...] Read more.

The underlying causes of denture stomatitis may be related to the long-term use of adhesives, which may predispose individuals to oral candidiasis. In this study, we hypothesize that antimicrobial peptides and antifungal antibiotics have diminished anti-Candida activities in denture adhesive. To show this, nine antimicrobial peptides and five antifungal antibiotics with and without 1.0% denture adhesive were incubated with Candida albicans strains ATCC 64124 and HMV4C in radial diffusion assays. In gels with 1.0% adhesive, HNP-1, HBD2, HBD3, IP-10, LL37 (only one strain), histatin 5 (only one strain), lactoferricin B, and SMAP28 showed diminished activity against C. albicans. In gels with 1.0% adhesive, amphotericin B and chlorhexidine dihydrochloride were active against both strains of C. albicans. These results suggest that denture adhesive may inactivate innate immune mediators in the oral cavity increasing the risk of C. albicans infections, but inclusion of antifungal antibiotics to denture adhesive may aid in prevention or treatment of Candida infections and denture stomatitis. Full article

9 pages, 4430 KiB

Open AccessArticle

Final Demonstration of the Co-Identity of Lipiarmycin A3 and Tiacumicin B (Fidaxomicin) through Single Crystal X-ray Analysis

by Stefano Serra^1,*

, Luciana Malpezzi², Angelo Bedeschi³, Claudio Fuganti¹ and Piera Fonte³

¹ Consiglio Nazionale delle Ricerche (C.N.R.), Istituto di Chimica del Riconoscimento Molecolare; Via L. Mancinelli 7, I-20131 Milano, Italy

² Dipartimento di Chimica, Materiali ed Ingegneria Chimica del Politecnico, Via Mancinelli 7, I-20131 Milano, Italy

³ OLON S.p.A, Strada Rivoltana 6/7, 20090 Rodano, Italy

Antibiotics 2017, 6(1), 7; https://doi.org/10.3390/antibiotics6010007 - 8 Feb 2017

Cited by 19 | Viewed by 7019

Abstract

Lipiarmycin A3 and tiacumicin B possess the same chemical structure and have been considered identical till recently, when some authors have suggested the possibility of a minor difference between the chemical structures of the two antibiotics. In this work we performed a comparative [...] Read more.

Lipiarmycin A3 and tiacumicin B possess the same chemical structure and have been considered identical till recently, when some authors have suggested the possibility of a minor difference between the chemical structures of the two antibiotics. In this work we performed a comparative X-ray analysis of lipiarmycin A3 and tiacumicin B. Although the commercial samples of the aforementioned compounds crystallize into two different crystal systems—evidently due to the different crystallization conditions—their chemical structures are identical. These results confirmed the previous assigned chemical structure of lipiarmycin A3 and its absolute configuration as well as its co-identity with the chemical structure of tiacumicin B, providing the definitive proof that these pharmaceutical compounds are identical in all respects. Full article

(This article belongs to the Special Issue Antibiotic Synthesis)

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14 pages, 3452 KiB

Open AccessArticle

Bulgecin A: The Key to a Broad‐Spectrum Inhibitor That Targets Lytic Transglycosylases

by Allison H. Williams^1,2,*, Richard Wheeler^1,2, Constance Thiriau^1,2, Ahmed Haouz³, Muhamed‐Kheir Taha⁴ and Ivo G. Boneca^1,2,*

¹ Institut Pasteur, Unité Biologie et génétique de la paroi bactérienne, Dept. Microbiologie, 28 Rue du Dr. Roux, 75015 Paris, France

² Institut National de la santé et de la Recherche Médicale (INSERM), Groupe Avenir, 75015 Paris, France

³ Institut Pasteur, CNRS‐UMR3528, Plate‐forme de Cristallographie, 25 Rue Dr. Roux, 75724 Paris, France

⁴ Institut Pasteur, Unité des Infection Bactériennes Invasives, Dept. Infection et Epidémiologie, 28 Rue du Dr. Roux, 75015 Paris, France

Antibiotics 2017, 6(1), 8; https://doi.org/10.3390/antibiotics6010008 - 22 Feb 2017

Cited by 30 | Viewed by 8185

Abstract

Lytic transglycosylases (Lts) are involved in recycling, cell division, and metabolism of the peptidoglycan. They have been understudied for their usefulness as potential antibacterial targets due to their high redundancy in Gram‐negative bacteria. Bulgecin A is an O‐sulphonated glycopeptide that targets primarily soluble [...] Read more.

Lytic transglycosylases (Lts) are involved in recycling, cell division, and metabolism of the peptidoglycan. They have been understudied for their usefulness as potential antibacterial targets due to their high redundancy in Gram‐negative bacteria. Bulgecin A is an O‐sulphonated glycopeptide that targets primarily soluble lytic tranglycosylases (Slt). It has been shown that bulgecin A increases the efficacy of β‐lactams that target penicillin bindings proteins (PBPs). Here, we present the high‐resolution crystal structure of LtgA from Neisseria meningitidis strain MC58, a membrane bound homolog of Escherichia coli Slt, in complex with bulgecin A. The LtgA‐bulgecin A complex reveals the mechanism of inhibition by bulgecin A at near atomic resolution. We further demonstrate that bulgecin A is not only a potent inhibitor of LtgA, but most importantly, it restores the efficacy of β‐lactam antibiotics in strains of N. meningitidis and Neisseria gonorrhoeae that have reduced susceptibility to β‐lactams. This is particularly relevant for N. gonorrhoeae where no vaccines are available. This work illustrates how best to target dangerous pathogens using a multiple drug target approach, a new and alternative approach to fighting antibiotic resistance. Full article

(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)

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11 pages, 979 KiB

Open AccessArticle

A Risk Assessment of Antibiotic Pan-Drug-Resistance in the UK: Bayesian Analysis of an Expert Elicitation Study

by Daniel Carter¹

, André Charlett¹, Stefano Conti¹, Julie V. Robotham¹, Alan P. Johnson^1,*

, David M. Livermore², Tom Fowler¹, Mike Sharland³, Susan Hopkins⁴

, Neil Woodford¹, Philip Burgess⁵

and Stephen Dobra⁵

¹ National Infection Service, Public Health England, London NW9 5EQ, UK

² Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK

³ Paediatric Infectious Diseases Research Group, St George’s University of London, Cranmer Terrace, London SW17 0RE, UK

⁴ Antimicrobial Resistance Programme, Public Health England, London NW9 5EQ, UK

⁵ Health Protection Analytical Team, Department of Health, Richmond House, 79 Whitehall, London SW1A 2NS, UK

Antibiotics 2017, 6(1), 9; https://doi.org/10.3390/antibiotics6010009 - 7 Mar 2017

Cited by 18 | Viewed by 6845

Abstract

To inform the UK antimicrobial resistance strategy, a risk assessment was undertaken of the likelihood, over a five-year time-frame, of the emergence and widespread dissemination of pan-drug-resistant (PDR) Gram-negative bacteria that would pose a major public health threat by compromising effective healthcare delivery. [...] Read more.

To inform the UK antimicrobial resistance strategy, a risk assessment was undertaken of the likelihood, over a five-year time-frame, of the emergence and widespread dissemination of pan-drug-resistant (PDR) Gram-negative bacteria that would pose a major public health threat by compromising effective healthcare delivery. Subsequent impact over five- and 20-year time-frames was assessed in terms of morbidity and mortality attributable to PDR Gram-negative bacteraemia. A Bayesian approach, combining available data with expert prior opinion, was used to determine the probability of the emergence, persistence and spread of PDR bacteria. Overall probability was modelled using Monte Carlo simulation. Estimates of impact were also obtained using Bayesian methods. The estimated probability of widespread occurrence of PDR pathogens within five years was 0.2 (95% credibility interval (CrI): 0.07–0.37). Estimated annual numbers of PDR Gram-negative bacteraemias at five and 20 years were 6800 (95% CrI: 400–58,600) and 22,800 (95% CrI: 1500–160,000), respectively; corresponding estimates of excess deaths were 1900 (95% CrI: 0–23,000) and 6400 (95% CrI: 0–64,000). Over 20 years, cumulative estimates indicate 284,000 (95% CrI: 17,000–1,990,000) cases of PDR Gram-negative bacteraemia, leading to an estimated 79,000 (95% CrI: 0–821,000) deaths. This risk assessment reinforces the need for urgent national and international action to tackle antibiotic resistance. Full article

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11 pages, 2358 KiB

Open AccessArticle

Activity of Sulfa Drugs and Their Combinations against Stationary Phase B. burgdorferi In Vitro

by Jie Feng, Shuo Zhang, Wanliang Shi and Ying Zhang^*

Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA

Antibiotics 2017, 6(1), 10; https://doi.org/10.3390/antibiotics6010010 - 22 Mar 2017

Cited by 17 | Viewed by 10074

Abstract

Lyme disease is a most common vector-borne disease in the US. Although the majority of Lyme patients can be cured with the standard two- to four-week antibiotic treatment, at least 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). [...] Read more.

Lyme disease is a most common vector-borne disease in the US. Although the majority of Lyme patients can be cured with the standard two- to four-week antibiotic treatment, at least 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, one possibility is that persisting organisms are not killed by current Lyme antibiotics. In our previous studies, we screened an FDA drug library and an NCI compound library on B. burgdorferi and found some drug hits including sulfa drugs as having good activity against B. burgdorferi stationary phase cells. In this study, we evaluated the relative activity of three commonly used sulfa drugs, sulfamethoxazole (Smx), dapsone (Dps), sulfachlorpyridazine (Scp), and also trimethoprim (Tmp), and assessed their combinations with the commonly prescribed Lyme antibiotics for activities against B. burgdorferi stationary phase cells. Using the same molarity concentration, dapsone, sulfachlorpyridazine and trimethoprim showed very similar activity against stationary phase B. burgdorferi enriched in persisters; however, sulfamethoxazole was the least active drug among the three sulfa drugs tested. Interestingly, contrary to other bacterial systems, Tmp did not show synergy in drug combinations with the three sulfa drugs at their clinically relevant serum concentrations against B. burgdorferi. We found that sulfa drugs combined with other antibiotics were more active than their respective single drugs and that four-drug combinations were more active than three-drug combinations. Four-drug combinations dapsone + minocycline + cefuroxime + azithromycin and dapsone + minocycline + cefuroxime + rifampin showed the best activity against stationary phase B. burgdorferi in these sulfa drug combinations. However, these four-sulfa-drug–containing combinations still had considerably less activity against B. burgdorferi stationary phase cells than the Daptomycin + cefuroxime + doxycycline used as a positive control which completely eradicated B. burgdorferi stationary phase cells. Future studies are needed to evaluate and optimize the sulfa drug combinations in vitro and also in animal models. Full article

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Review

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14 pages, 1054 KiB

Open AccessReview

Thioridazine: A Non-Antibiotic Drug Highly Effective, in Combination with First Line Anti-Tuberculosis Drugs, against Any Form of Antibiotic Resistance of Mycobacterium tuberculosis Due to Its Multi-Mechanisms of Action

by Leonard Amaral^1,2,*

and Miguel Viveiros³

¹ Insititute of Hygiene and Tropical Medicine, Universidade Nova de Lisboa, Lisbon 1349-008, Portugal

² Institute of Medical Microbiology and Immunobiology, University of Szeged, Szeged 6720, Hungary

³ Unidade de Microbiologia Médica, Global Health and Tropical Medicine, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon 1349-008, Portugal

Antibiotics 2017, 6(1), 3; https://doi.org/10.3390/antibiotics6010003 - 14 Jan 2017

Cited by 53 | Viewed by 12081

Abstract

This review presents the evidence that supports the use of thioridazine (TZ) for the therapy of a pulmonary tuberculosis infection regardless of its antibiotic resistance status. The evidence consists of in vitro and ex vivo assays that demonstrate the activity of TZ against [...] Read more.

This review presents the evidence that supports the use of thioridazine (TZ) for the therapy of a pulmonary tuberculosis infection regardless of its antibiotic resistance status. The evidence consists of in vitro and ex vivo assays that demonstrate the activity of TZ against all encountered Mycobacterium tuberculosis (Mtb) regardless of its antibiotic resistance phenotype, as well as in vivo as a therapy for mice infected with multi-drug resistant strains of Mtb, or for human subjects infected with extensively drug resistant (XDR) Mtb. The mechanisms of action by which TZ brings about successful therapeutic outcomes are presented in detail. Full article

(This article belongs to the Special Issue Discover New Antibiotics 2016)

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