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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (15 March 2019) | Viewed by 37974

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Special Issue Editor

Prof. Dr. Francesc Rabanal Anglada

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Guest Editor

Organic Chemistry Section, Department of Inorganic and Organic Chemistry, Faculty of Chemistry, University of Barcelona, 08028 Barcelona, Spain
Interests: design and chemical synthesis of AMPs (Polymyxin B) and peptidomimetics; β-Lactam antibiotics; antimicrobial resistance; gram-negative bacterial infections

Special Issue Information

Dear Colleagues,

Polymyxins, which include colistin (polymyxin E), are a class of cyclic lipopeptide antibiotics that are highly active against therapeutically relevant Gram-negative bacteria, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, and Escherichia coli. Discovered in 1947, polymyxins became available in the 1950s and were used in the clinic for a couple of decades. At the end of the 1970s, though, they were progressively abandoned due to neurotoxicity and nephrotoxicity concerns and because less toxic therapeutic options became available.

The emergence of bacteria that are resistant to almost all available antibiotics and the fact that no novel drugs have been designed or discovered in the last years, have renewed the interest in this old class of antibiotics and are currently used as last-line therapy for otherwise untreatable infections.

This Special Issue is devoted to recent developments in the field of polymyxins research and development. The scope is broad, including chemistry of polymyxins, design of new analogues, evaluation of microbiological, pharmacological, and toxicological profiles, mechanism of action, resistance, antibiofilm properties, antimicrobial synergy, sensitization, nanoconjugation and in vitro and in vivo assays.

The idea of this issue is to become a platform to update and share the knowledge in this important field of antibiotic research and development.

Prof. Francesc Rabanal Anglada
Guest Editor

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Keywords

polymyxins
colistin
chemistry
design
development
activity
toxicity
pharmacology
biomarkers
probes
nanoconjugation
sensitization
permeabilization
polymyxin/colistin resistance
antibiofilm activity
biophysics
mechanism of action
in vitro assays
in vivo assays

Published Papers (6 papers)

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Research

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12 pages, 1775 KiB

Open AccessArticle

In-Vitro Evaluation of Different Antimicrobial Combinations with and without Colistin Against Carbapenem-Resistant Acinetobacter Baumannii

by Alessandra Oliva, Stefania Garzoli, Massimiliano De Angelis, Carolina Marzuillo, Vincenzo Vullo, Claudio M. Mastroianni and Rino Ragno

Molecules 2019, 24(5), 886; https://doi.org/10.3390/molecules24050886 - 03 Mar 2019

Cited by 12 | Viewed by 3892

Abstract

Carbapenem-resistant Acinetobacter baumannii (CR-Ab) infections are associated with high morbidity and mortality. The aim of the study was to evaluate the in-vitro activity of different antimicrobial combinations (with and without colistin, COL) against clinical isolates of CR-Ab collected from patients with CR-Ab infection, including unconventional combinations such as COL + VANcomycin (VAN) and COL + rifampin (RIF). CR-Ab strains were collected from hospitalized patients at Sapienza University of Rome. Antimicrobial susceptibility patterns were determined throughout MIC50/90s whereas the synergistic activity was evaluated by qualitative (i.e., checkerboard) and quantitative (i.e., killing studies) methods. All the strains were found oxacillinase (OXA) producers and tigecycline (TIG) sensitive whereas 2 strains were resistant to COL. Application of the checkerboard method indicated complete synergism in COL combinations at different extension: 21.4%, 57.1%, 42.8%, 35.7% for COL + meropenem (MEM), COL + RIF, COL + VAN and COL + TIG, respectively, with the non-conventional combinations COL + VAN and COL + RIF exhibiting the highest rate of synergism. Regarding COL-free combination, complete synergism was observed in 35.7% of the strains for MEM + TIG. Killing studies showed that the combinations COL + MEM, COL + TIG and MEM + TIG were bactericidal and synergistic against both colistin-sensitive and low colistin-resistant strains whereas only the combinations COL + VAN and COL + RIF showed an early and durable bactericidal activity against all the tested strains, with absence of growth at 24 h. This study demonstrated that COL-based combinations lead to a high level of synergic and bactericidal activity, especially COL + VAN and COL + RIF, even in the presence of high level of COL resistance. Full article

(This article belongs to the Special Issue Polymyxins)

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13 pages, 1326 KiB

Open AccessFeature PaperArticle

Structure-Function Studies of Polymyxin B Lipononapeptides

by Alejandra Gallardo-Godoy, Karl A. Hansford, Craig Muldoon, Bernd Becker, Alysha G. Elliott, Johnny X. Huang, Ruby Pelingon, Mark S. Butler, Mark A. T. Blaskovich and Matthew A. Cooper

Molecules 2019, 24(3), 553; https://doi.org/10.3390/molecules24030553 - 02 Feb 2019

Cited by 24 | Viewed by 6009

Abstract

The emerging threat of infections caused by highly drug-resistant bacteria has prompted a resurgence in the use of the lipodecapeptide antibiotics polymyxin B and colistin as last resort therapies. Given the emergence of resistance to these drugs, there has also been a renewed interest in the development of next generation polymyxins with improved therapeutic indices and spectra of action. We report structure-activity studies of 36 polymyxin lipononapeptides structurally characterised by an exocyclic FA-Thr²-Dab³ lipodipeptide motif instead of the native FA-Dab¹-Thr²-Dab³ tripeptide motif found in polymyxin B, removing one of the positively charged residues believed to contribute to nephrotoxicity. The compounds were prepared by solid phase synthesis using an on-resin cyclisation approach, varying the fatty acid and the residues at position 2 (P2), P3 and P4, then assessing antimicrobial potency against a panel of Gram-negative bacteria, including polymyxin-resistant strains. Pairwise comparison of N-acyl nonapeptide and decapeptide analogues possessing different fatty acids demonstrated that antimicrobial potency is strongly influenced by the N-terminal L-Dab-1 residue, contingent upon the fatty acid. This study highlights that antimicrobial potency may be retained upon truncation of the N-terminal L-Dab-1 residue of the native exocyclic lipotripeptide motif found in polymyxin B. The strategy may aid in the design of next generation polymyxins. Full article

(This article belongs to the Special Issue Polymyxins)

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12 pages, 398 KiB

Open AccessArticle

Colistin Use in Patients with Chronic Kidney Disease: Are We Underdosing Patients?

by Luisa Sorli, Sonia Luque, Jian Li, Eva Rodríguez, Nuria Campillo, Xenia Fernandez, Jade Soldado, Ignacio Domingo, Milagro Montero, Santiago Grau and Juan P. Horcajada

Molecules 2019, 24(3), 530; https://doi.org/10.3390/molecules24030530 - 01 Feb 2019

Cited by 7 | Viewed by 3755

Abstract

Colistin is administered as its inactive prodrug colistimethate (CMS). Selection of an individualized CMS dose for each patient is difficult due to its narrow therapeutic window, especially in patients with chronic kidney disease (CKD). Our aim was to analyze CMS use in patients with CKD. Secondary objectives were to assess the safety and efficacy of CMS in this special population. In this prospective observational cohort study of CMS-treated CKD patients, CKD was defined as the presence of a glomerular filtration rate (GFR) < 60 mL/min/m² for more than 3 months. The administered doses of CMS were compared with those recently published in the literature. Worsened CKD at the end of treatment (EOT) was evaluated with the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria. Colistin plasma concentrations (C_ss) were measured using high-performance liquid chromatography. Fifty-nine patients were included. Thirty-six (61.2%) were male. The median age was 76 (45–95) years and baseline GFR was 36.6 ± 13.6. The daily mean CMS dosage used was compared with recently recommended doses (3.36 vs. 6.07; p < 0.001). Mean C_ss was 0.9 (0.2–2.9) mg/L, and C_ss was <2 mg/L in 50 patients (83.3%). Clinical cure was achieved in 43 (72.9%) patients. Worsened renal function at EOT was present in 20 (33.9%) patients and was reversible in 10 (52.6%). The CMS dosages used in this cohort were almost half those currently recommended. The mean achieved C_ss were under the recommended target of 2 mg/dL. Despite this, clinical cure rate was high. In this patient cohort, the incidence of nephrotoxicity was similar to those found in other recent studies performed in the general population and was reversible in 52.6%. These results suggest that CMS is safe and effective in patients with CKD and may encourage physicians to adjust dosage regimens to recent recommendations in order to optimize CMS treatments. Full article

(This article belongs to the Special Issue Polymyxins)

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15 pages, 2118 KiB

Open AccessArticle

Enhanced NADH Metabolism Involves Colistin-Induced Killing of Bacillus subtilis and Paenibacillus polymyxa

by Zhiliang Yu, Yuyi Zhu, Jianv Fu, Juanping Qiu and Jianhua Yin

Molecules 2019, 24(3), 387; https://doi.org/10.3390/molecules24030387 - 22 Jan 2019

Cited by 22 | Viewed by 4153

Abstract

The commonly believed mechanism of colistin against Gram-negative bacteria is to cause cell membrane lysis, whereas the mechanism of colistin against Gram-positive bacteria is extremely fragmented. In this study, we found that colistin treatment on Bacillus subtilis WB800, Paenibacillus polymyxa C12 and Paenibacillus polymyxa ATCC842 enhances not only the activities of α-ketoglutaric dehydrogenase and malate dehydrogenase in tricarboxylic acid (TCA) cycle, but also the relative expression levels of their encoding genes. Additionally, the oxaloacetate concentration also increases. Interestingly, the analysis of the relative expression of genes specific for respiratory chain showed that colistin treatment stimulates the respiratory chain in Gram-positive bacteria. Accordingly, the NAD⁺/NADH ratio increases and the oxidative level is then boosted up. As a result, the intensive oxidative damages are induced in Gram-positive bacteria and cells are killed. Notably, both rotenone and oligomycin, respectively, inhibiting NADH dehydrogenase and phosphorylation on respiratory chain can downgrade oxidative stress formation, thus alleviating the colistin-induced killing of Gram-positive cells. Besides, thiourea-based scavenging for reactive oxygen species also rescues the colistin-subjected cells. These data collectively demonstrate that colistin stimulates both TCA cycle and respiratory chain in Gram-positive bacteria, leading to the enhancement of NADH metabolism and resulting in the generation of oxidative damages in Gram-positive cells. Our studies provide a better understanding of antibacterial mechanism of colistin against Gram-positive bacteria, which is important for knowledge on bacterial resistance to colistin happening via the inhibition of respiratory chain and manipulation of its production. Full article

(This article belongs to the Special Issue Polymyxins)

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Review

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14 pages, 1433 KiB

Open AccessReview

Molecular Mechanisms of Colistin-Induced Nephrotoxicity

by Zhibo Gai, Sophia L. Samodelov, Gerd A. Kullak-Ublick and Michele Visentin

Molecules 2019, 24(3), 653; https://doi.org/10.3390/molecules24030653 - 12 Feb 2019

Cited by 78 | Viewed by 8619

Abstract

The emergence of multidrug resistant (MDR) infections and the shortage of new therapeutic options have made colistin, a polymyxin antibiotic, the main option for the treatment of MDR Gram-negative bacterial infections in the last decade. However, the rapid onset of renal damage often prevents the achievement of optimal therapeutic doses and/or forces the physicians to interrupt the therapy, increasing the risk of drug resistance. The proper management of colistin-induced nephrotoxicity remains challenging, mostly because the investigation of the cellular and molecular pharmacology of this drug, off the market for decades, has been largely neglected. For years, the renal damage induced by colistin was considered a mere consequence of the detergent activity of this drug on the cell membrane of proximal tubule cells. Lately, it has been proposed that the intracellular accumulation is a precondition for colistin-mediated renal damage, and that mitochondria might be a primary site of damage. Antioxidant approaches (e.g., ascorbic acid) have shown promising results in protecting the kidney of rodents exposed to colistin, yet none of these strategies have yet reached the bedside. Here we provide a critical overview of the possible mechanisms that may contribute to colistin-induced renal damage and the potential protective strategies under investigation. Full article

(This article belongs to the Special Issue Polymyxins)

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15 pages, 1026 KiB

Open AccessFeature PaperReview

Polymyxin Derivatives that Sensitize Gram-Negative Bacteria to Other Antibiotics

by Martti Vaara

Molecules 2019, 24(2), 249; https://doi.org/10.3390/molecules24020249 - 11 Jan 2019

Cited by 90 | Viewed by 10926

Abstract

Polymyxins (polymyxin B (PMB) and polymyxin E (colistin)) are cyclic lipodecapeptide antibiotics, highly basic due to five free amino groups, and rapidly bactericidal against Gram-negative bacteria, such as the majority of Enterobacteriaceae as well as Acinetobacter baumannii and Pseudomonas aeruginosa. Their clinical use was abandoned in the 1960s because of nephrotoxicity and because better-tolerated drugs belonging to other antibiotic classes were introduced. Now, due to the global dissemination of extremely-drug resistant Gram-negative bacterial strains, polymyxins have resurged as the last-line drugs against those strains. Novel derivatives that are less toxic and/or more effective at tolerable doses are currently under preclinical development and their properties have recently been described in several extensive reviews. Other derivatives lack any direct bactericidal activity but damage the outermost permeability barrier, the outer membrane, of the target bacteria and make it more permeable to many other antibiotics. This review describes the properties of three thus far best-characterized “permeabilizer” derivatives, i.e., the classic permeabilizer polymyxin B nonapeptide (PMBN), NAB7061, and SPR741/NAB741, a compound that recently successfully passed the clinical phase 1. Also, a few other permeabilizer compounds are brought up. Full article

(This article belongs to the Special Issue Polymyxins)

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