Pharmacology and Therapeutics - Research Publications
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ItemThe impact of backbone N-methylation on the structure-activity relationship of Leu10-teixobactin(WILEY, 2019-09)Antimicrobial resistance is a serious threat to global human health; therefore, new anti-infective therapeutics are required. The cyclic depsi-peptide teixobactin exhibits potent antimicrobial activity against several Gram-positive pathogens. To study the natural product's mechanism of action and improve its pharmacological properties, efficient chemical methods for preparing teixobactin analogues are required to expedite structure-activity relationship studies. Described herein is a synthetic route that enables rapid access to analogues. Furthermore, our new N-methylated analogues highlight that hydrogen bonding along the N-terminal tail is likely to be important for antimicrobial activity.
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ItemA Portrait of the Sialyl Glycan Receptor Specificity of the H10 Influenza Virus Hemagglutinin-A Picture of an Avian Virus on the Verge of Becoming a Pandemic?(MDPI, 2017-12)Pandemic influenza is a constant global threat to human health. In particular, the pandemic potential of novel avian influenza viruses such as the H10N7 and H10N8 avian strains, which recently managed to cross the species barrier from birds to humans, are always of great concern as we are unlikely to have any prior immunity. Human and avian isolates of H10 influenza display the ability to rapidly adapt to replication in mammalian hosts. Fortunately, so far there is no evidence of efficient human-to-human transmission of any avian influenza virus. This review examines all of the available clinical and biological data for H10 influenza viruses with an emphasis on hemagglutinin as it is a major viral antigen that determines host range and immunity. The available glycan binding data on the influenza H10 hemagglutinin are discussed in a structure-recognition perspective. Importantly, this review raises the question of whether the emerging novel avian H10 influenza viruses truly represents a threat to global health that warrants close monitoring.
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ItemSynergistic Combination of Polymyxin B and Enrofloxacin Induced Metabolic Perturbations in Extensive Drug-Resistant Pseudomonas aeruginosa(FRONTIERS MEDIA SA, 2019-10-03)Polymyxins are used as a last-resort class of antibiotics against multidrug-resistant (MDR) Gram-negative Pseudomonas aeruginosa. As polymyxin monotherapy is associated with potential development of resistance, combination therapy is highly recommended. This study investigated the mechanism underlying the synergistic killing of polymyxin B and enrofloxacin against extensive drug-resistant (XDR) P. aeruginosa. An XDR isolate P. aeruginosa 12196 was treated with clinically relevant concentrations of polymyxin B (2 mg/L) and enrofloxacin (1 mg/L) alone or in combination. Metabolome profiles were investigated from bacterial samples collected at 1-and 4-h posttreatment using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and data were analyzed using univariate and multivariate statistics. Significantly perturbed metabolites (q < 0.05, fold change ≥ 2) were subjected to pathway analysis. The synergistic killing by polymyxin B-enrofloxacin combination was initially driven by polymyxin B as indicated by the perturbation of lipid metabolites at 1 h in particular. The killing was subsequently driven by enrofloxacin via the inhibition of DNA replication, resulting in the accumulation of nucleotides at 4 h. Furthermore, the combination uniquely altered levels of metabolites in energy metabolism and cell envelope biogenesis. Most importantly, the combination significantly minimized polymyxin resistance via the inhibition of lipid A modification pathway, which was most evident at 4 h. This is the first study to elucidate the synergistic mechanism of polymyxin B-enrofloxacin combination against XDR P. aeruginosa. The metabolomics approach taken in this study highlights its power to elucidate the mechanism of synergistic killing by antibiotic combinations at the systems level.
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ItemGlobal metabolic analyses identify key differences in metabolite levels between polymyxin-susceptible and polymyxin-resistant Acinetobacter baumannii(NATURE PORTFOLIO, 2016-02-29)Multidrug-resistant Acinetobacter baumannii presents a global medical crisis and polymyxins are used as the last-line therapy. This study aimed to identify metabolic differences between polymyxin-susceptible and polymyxin-resistant A. baumannii using untargeted metabolomics. The metabolome of each A. baumannii strain was measured using liquid chromatography-mass spectrometry. Multivariate and univariate statistics and pathway analyses were employed to elucidate metabolic differences between the polymyxin-susceptible and -resistant A. baumannii strains. Significant differences were identified between the metabolic profiles of the polymyxin-susceptible and -resistant A. baumannii strains. The lipopolysaccharide (LPS) deficient, polymyxin-resistant 19606R showed perturbation in specific amino acid and carbohydrate metabolites, particularly pentose phosphate pathway (PPP) and tricarboxylic acid (TCA) cycle intermediates. Levels of nucleotides were lower in the LPS-deficient 19606R. Furthermore, 19606R exhibited a shift in its glycerophospholipid profile towards increased abundance of short-chain lipids compared to the parent polymyxin-susceptible ATCC 19606. In contrast, in a pair of clinical isolates 03-149.1 (polymyxin-susceptible) and 03-149.2 (polymyxin-resistant, due to modification of lipid A), minor metabolic differences were identified. Notably, peptidoglycan biosynthesis metabolites were significantly depleted in both of the aforementioned polymyxin-resistant strains. This is the first comparative untargeted metabolomics study to show substantial differences in the metabolic profiles of the polymyxin-susceptible and -resistant A. baumannii.
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ItemProbing the Penetration of Antimicrobial Polymyxin Lipopeptides into Gram-Negative Bacteria(AMER CHEMICAL SOC, 2014-04)The dry antibiotic development pipeline coupled with the emergence of multidrug resistant Gram-negative 'superbugs' has driven the revival of the polymyxin lipopeptide antibiotics. Polymyxin resistance implies a total lack of antibiotics for the treatment of life-threatening infections. The lack of molecular imaging probes that possess native polymyxin-like antibacterial activity is a barrier to understanding the resistance mechanisms and the development of a new generation of polymyxin lipopeptides. Here we report the regioselective modification of the polymyxin B core scaffold at the N-terminus with the dansyl fluorophore to generate an active probe that mimics polymyxin B pharmacologically. Time-lapse laser scanning confocal microscopy imaging of the penetration of probe (1) into Gram-negative bacterial cells revealed that the probe initially accumulates in the outer membrane and subsequently penetrates into the inner membrane and finally the cytoplasm. The implementation of this polymyxin-mimetic probe will advance the development of platforms for the discovery of novel polymyxin lipopeptides with efficacy against polymyxin-resistant strains.
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ItemAnthelmintic closantel enhances bacterial killing of polymyxin B against multidrug-resistant Acinetobacter baumannii(NATURE PUBLISHING GROUP, 2016-06)Polymyxins, an old class of antibiotics, are currently used as the last resort for the treatment of multidrug-resistant (MDR) Acinetobacter baumannii. However, recent pharmacokinetic and pharmacodynamic data indicate that monotherapy can lead to the development of resistance. Novel approaches are urgently needed to preserve and improve the efficacy of this last-line class of antibiotics. This study examined the antimicrobial activity of novel combination of polymyxin B with anthelmintic closantel against A. baumannii. Closantel monotherapy (16 mg l(-1)) was ineffective against most tested A. baumannii isolates. However, closantel at 4-16 mg l(-1) with a clinically achievable concentration of polymyxin B (2 mg l(-1)) successfully inhibited the development of polymyxin resistance in polymyxin-susceptible isolates, and provided synergistic killing against polymyxin-resistant isolates (MIC ⩾4 mg l(-1)). Our findings suggest that the combination of polymyxin B with closantel could be potentially useful for the treatment of MDR, including polymyxin-resistant, A. baumannii infections. The repositioning of non-antibiotic drugs to treat bacterial infections may significantly expedite discovery of new treatment options for bacterial 'superbugs'.
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ItemComparative Metabolomics Reveals Key Pathways Associated With the Synergistic Killing of Colistin and Sulbactam Combination Against Multidrug-Resistant Acinetobacter baumannii(FRONTIERS MEDIA SA, 2019-07-04)Background: Polymyxins are a last-line class of antibiotics against multidrug-resistant Acinetobacter baumannii. However, polymyxin resistance can emerge with monotherapy, highlighting the need for synergistic combination therapies. Polymyxins in combination with β-lactams have shown remarkable synergy against multidrug-resistant A. baumannii. Methods: Liquid chromatography-mass spectrometry-based metabolomics was conducted to investigate the metabolic perturbations in an A. baumannii clinical isolate, AB090342, in response to colistin (1 mg/L), sulbactam (128 mg/L), and their combination at 1, 4, and 24 h. Metabolomics data were analyzed using univariate and multivariate statistics, and metabolites showing ≥2-fold changes were subjected to pathway analysis. Results: The synergistic activity of colistin-sulbactam combination was initially driven by colistin through perturbation of fatty acid and phospholipid levels at 1 h. Cell wall biosynthesis was perturbed by sulbactam alone and the combination over 24 h; this was demonstrated by the decreased levels of two important precursors, uridine diphosphate-N-acetylglucosamine and uridine diphosphate-N-acetylmuramate, together with perturbed lysine and amino sugar metabolism. Moreover, sulbactam alone and the combination significantly depleted nucleotide metabolism and the associated arginine biosynthesis, glutamate metabolism, and pentose phosphate pathway. Notably, the colistin-sulbactam combination decreased amino acid and nucleotide levels more dramatically at 4 h compared with both monotherapies. Conclusions: This is the first metabolomics study revealing the time-dependent synergistic activity of colistin and sulbactam against A. baumannii, which was largely driven by sulbactam through the inhibition of cell wall biosynthesis. Our mechanistic findings may help optimizing synergistic colistin combinations in patients.
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ItemThe thermodynamics of Pr55Gag-RNA interaction regulate the assembly of HIV(PUBLIC LIBRARY SCIENCE, 2017-02)The interactions that occur during HIV Pr55Gag oligomerization and genomic RNA packaging are essential elements that facilitate HIV assembly. However, mechanistic details of these interactions are not clearly defined. Here, we overcome previous limitations in producing large quantities of full-length recombinant Pr55Gag that is required for isothermal titration calorimetry (ITC) studies, and we have revealed the thermodynamic properties of HIV assembly for the first time. Thermodynamic analysis showed that the binding between RNA and HIV Pr55Gag is an energetically favourable reaction (ΔG<0) that is further enhanced by the oligomerization of Pr55Gag. The change in enthalpy (ΔH) widens sequentially from: (1) Pr55Gag-Psi RNA binding during HIV genome selection; to (2) Pr55Gag-Guanosine Uridine (GU)-containing RNA binding in cytoplasm/plasma membrane; and then to (3) Pr55Gag-Adenosine(A)-containing RNA binding in immature HIV. These data imply the stepwise increments of heat being released during HIV biogenesis may help to facilitate the process of viral assembly. By mimicking the interactions between A-containing RNA and oligomeric Pr55Gag in immature HIV, it was noted that a p6 domain truncated Pr50Gag Δp6 is less efficient than full-length Pr55Gag in this thermodynamic process. These data suggest a potential unknown role of p6 in Pr55Gag-Pr55Gag oligomerization and/or Pr55Gag-RNA interaction during HIV assembly. Our data provide direct evidence on how nucleic acid sequences and the oligomeric state of Pr55Gag regulate HIV assembly.
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ItemPharmacokinetics and relative bioavailability of an oral amoxicillin-apramycin combination in pigs(PUBLIC LIBRARY SCIENCE, 2017-04-20)A new compound granular premix of amoxicillin (20% w/w dry mass)/apramycin (5% w/w dry mass) was developed, and its pharmacokinetics and relative bioavailability were determined in pigs following oral administration following a cross-over study design. The pharmacokinetic parameters of amoxicillin (t1/2λ = 6.43 ± 4.85h, Cmax = 3.2 ± 1.35 μg·mL-1, Tmax = 1.92 ± 0.58, AUCINF = 8.98 ± 2.11 h·μg·mL-1) and apramycin (t1/2λ = 8.67±4.4h, Cmax = 0.23 ± 0.12 μg·mL-1, Tmax = 2.25 ± 0.82 h, AUCINF = 12.37 ± 8.64h·μg·mL-1) when administered as the amoxicillin-apramycin granular premix did not significantly differ from those for the single-ingredient powder form of each component. The relative bioavailability of amoxicillin following oral administration of the amoxicillin-apramycin granular premix was 22.62% when compared to the intramuscular administration of commercial amoxicillin sodium-powder. This is the first report of a new amoxicillin-apramycin combination which has a potential veterinary application the for prevention and treatment digestive tract infections in pigs.
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ItemSignificant Accumulation of Polymyxin in Single Renal Tubular Cells: A Medicinal Chemistry and Triple Correlative Microscopy Approach(AMER CHEMICAL SOC, 2015-02-03)Polymyxin is the last-line therapy against Gram-negative 'superbugs'; however, dose-limiting nephrotoxicity can occur in up to 60% of patients after intravenous administration. Understanding the accumulation and concentration of polymyxin within renal tubular cells is essential for the development of novel strategies to ameliorate its nephrotoxicity and to develop safer, new polymyxins. We designed and synthesized a novel dual-modality iodine-labeled fluorescent probe for quantitative mapping of polymyxin in kidney proximal tubular cells. Measured by synchrotron X-ray fluorescence microscopy, polymyxin concentrations in single rat (NRK-52E) and human (HK-2) kidney tubular cells were approximately 1930- to 4760-fold higher than extracellular concentrations. Our study is the first to quantitatively measure the significant uptake of polymyxin in renal tubular cells and provides crucial information for the understanding of polymyxin-induced nephrotoxicity. Importantly, our approach represents a significant methodological advancement in determination of drug uptake for single-cell pharmacology.