30 results on '"Venter H"'
Search Results
2. Conceptual Model for Crowd-Sourcing Digital Forensic Evidence
- Author
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Baror, Stacey O., Venter, H. S., Kebande, Victor R., Kacprzyk, Janusz, Series Editor, Gomide, Fernando, Advisory Editor, Kaynak, Okyay, Advisory Editor, Liu, Derong, Advisory Editor, Pedrycz, Witold, Advisory Editor, Polycarpou, Marios M., Advisory Editor, Rudas, Imre J., Advisory Editor, Wang, Jun, Advisory Editor, Ben Ahmed, Mohamed, editor, Boudhir, Anouar Abdelhakim, editor, Karaș, İsmail Rakıp, editor, Jain, Vipul, editor, and Mellouli, Sehl, editor
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- 2022
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3. Conceptual Model for Crowd-Sourcing Digital Forensic Evidence
- Author
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Baror, Stacey O., primary, Venter, H. S., additional, and Kebande, Victor R., additional
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- 2022
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4. Genomic profiling of Pasteurella multocida isolated from feedlot cases of bovine respiratory disease.
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Alhamami, T, Roy Chowdhury, P, Venter, H, Veltman, T, Truswell, A, Abraham, S, Sapula, SA, Carr, M, Djordjevic, SP, Trott, DJ, Alhamami, T, Roy Chowdhury, P, Venter, H, Veltman, T, Truswell, A, Abraham, S, Sapula, SA, Carr, M, Djordjevic, SP, and Trott, DJ
- Abstract
Pasteurella multocida causes a range of diseases in many host species throughout the world, including bovine respiratory disease (BRD) which is predominantly seen in feedlot cattle. This study assessed genetic diversity among 139 P. multocida isolates obtained from post-mortem lung swabs of BRD-affected feedlot cattle in four Australian states: New South Wales, Queensland, South Australia, and Victoria during 2014-2019. Whole-genome sequencing (WGS) was used to determine capsular serogroup, lipopolysaccharide genotypes, multi-locus sequence types and phylogenetic relationships. Two capsular types (A and D), with most isolates (132/139; 95%) belonging to type A; and three lipopolysaccharide (LPS) genotypes were identified (L1 [6/139; 4.3%], L3 [124/139; 89.2%] and L6 [9/139; 6.4%)]). Multi-locus sequence types (STs) ST9, ST13, ST17, ST20, ST36, ST50, ST58, ST79, ST124, ST125, ST132, ST167, ST185, ST327, ST394, and three novel STs [ST396, ST397, and ST398] were identified, with ST394 (59/139; 42.4%) and ST79 (44/139; 32%) the most prevalent in all four states. Isolates displaying phenotypic resistance to single, dual or multiple antibiotics (macrolide, tetracycline and aminopenicillins) were predominantly ST394 (23/139; 17%). Laterally mobile elements identified in the resistant ST394 isolates included small plasmids, encoding macrolide and/or tetracycline resistance, distributed in all states; and chromosomally located integrative conjugative elements (ICEs) (4 ST394 and 1 ST125) from the same Queensland feedlot. This study highlights the genomic diversity, epidemiological relationships and AMR associations in bovine P. multocida isolates from Australia and provides insight into the unique ST prevalence compared to other major beef-producing countries.
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- 2023
5. Correction: Alhamami et al. First Emergence of Resistance to Macrolides and Tetracycline Identified in Mannheimia haemolytica and Pasteurella multocida Isolates from Beef Feedlots in Australia. Microorganisms 2021, 9, 1322
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Alhamami, T, Roy Chowdhury, P, Gomes, N, Carr, M, Veltman, T, Khazandi, M, Mollinger, J, Deutscher, AT, Turni, C, Mahdi, L, Venter, H, Abraham, S, Djordjevic, SP, and Trott, DJ
- Abstract
The authors wish to make the following corrections to this paper [...].
- Published
- 2022
6. Antimicrobial susceptibility and genomic analysis of Histophilus somni isolated from cases of bovine respiratory disease in Autralian feedlot cattle
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Alhamami, T., Low, W.Y., Ren, Y., Taylor, K., Khazandi, M., Veltman, T., Venter, H., Carr, M., Turni, C., Abraham, S., Trott, D.J., Alhamami, T., Low, W.Y., Ren, Y., Taylor, K., Khazandi, M., Veltman, T., Venter, H., Carr, M., Turni, C., Abraham, S., and Trott, D.J.
- Abstract
Histophilus somni is a prevalent commensal organism of the upper respiratory tract of cattle and a major causative agent of bovine respiratory disease (BRD) and other syndromes including myocarditis and infectious thromboembolic meningoencephalitis. This study investigated the antimicrobial susceptibility and phylogenetic relationships of H. somni isolates obtained from lung, heart, and other tissues at post-mortem as well as nasal mucosa swabs from cases of BRD in Australian feedlots (2004–2019). Broth microdilution Minimal Inhibitory Concentration (MIC) assays were determined for 19 antimicrobials using three different media (CLSI approved Veterinary Fastidious Medium [VFM], Mueller-Hinton fastidious broth medium supplemented with yeast extract [MHF-Y] and Columbia Broth [CB] supplemented with 5% lysed horse blood). For all antimicrobials, MICs obtained using CB medium were identical or within 1 dilution step of the MICs obtained for VFM and MHF-Y media. Therefore, CB may be a suitable medium for H. somni antimicrobial susceptibility testing similar to MHF-Y medium. None of the 70 Australian H. somni isolates exhibited resistance to antimicrobials with CLSI breakpoints including those commonly used in the treatment of BRD in Australia (first-line tetracyclines [chlortetracycline and oxytetracycline], second-line macrolides [tulathromycin], and third-line extended-spectrum cephalosporin [ceftiofur]). Whole-genome sequence analysis of 65 H. somni isolates for genomic single nucleotide polymorphism differences identified four phylogenetic clusters, each containing isolates from different Australian states, feedlots and tissue sources that clustered together. These findings demonstrate limited genetic diversity and the absence of significant antimicrobial resistance among Australian isolates of H. somni isolated from feedlot cattle.
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- 2022
7. Correction: Alhamami et al. First emergence of resistance to macrolides and tetracycline identified in Mannheimia haemolytica and Pasteurella multocida isolates from beef feedlots in Australia. Microorganisms 2021, 9, 1322
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Alhamami, T., Roy Chowdhury, P., Gomes, N., Carr, M., Veltman, T., Khazandi, M., Mollinger, J., Deutscher, A.T., Turni, C., Mahdi, L., Venter, H., Abraham, S., Djordjevic, S.P., Trott, D.J., Alhamami, T., Roy Chowdhury, P., Gomes, N., Carr, M., Veltman, T., Khazandi, M., Mollinger, J., Deutscher, A.T., Turni, C., Mahdi, L., Venter, H., Abraham, S., Djordjevic, S.P., and Trott, D.J.
- Abstract
The authors wish to make the following corrections to this paper...
- Published
- 2022
8. Targeting malaria parasites with novel derivatives of azithromycin
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Burns, AL, Sleebs, BE, Gancheva, M, McLean, KT, Siddiqui, G, Venter, H, Beeson, JG, O'Handley, R, Creek, DJ, Ma, S, Froelich, S, Goodman, CD, McFadden, G, Wilson, DW, Burns, AL, Sleebs, BE, Gancheva, M, McLean, KT, Siddiqui, G, Venter, H, Beeson, JG, O'Handley, R, Creek, DJ, Ma, S, Froelich, S, Goodman, CD, McFadden, G, and Wilson, DW
- Abstract
INTRODUCTION: The spread of artemisinin resistant Plasmodium falciparum parasites is of global concern and highlights the need to identify new antimalarials for future treatments. Azithromycin, a macrolide antibiotic used clinically against malaria, kills parasites via two mechanisms: 'delayed death' by inhibiting the bacterium-like ribosomes of the apicoplast, and 'quick-killing' that kills rapidly across the entire blood stage development. METHODS: Here, 22 azithromycin analogues were explored for delayed death and quick-killing activities against P. falciparum (the most virulent human malaria) and P. knowlesi (a monkey parasite that frequently infects humans). RESULTS: Seventeen analogues showed improved quick-killing against both Plasmodium species, with up to 38 to 20-fold higher potency over azithromycin after less than 48 or 28 hours of treatment for P. falciparum and P. knowlesi, respectively. Quick-killing analogues maintained activity throughout the blood stage lifecycle, including ring stages of P. falciparum parasites (<12 hrs treatment) and were >5-fold more selective against P. falciparum than human cells. Isopentenyl pyrophosphate supplemented parasites that lacked an apicoplast were equally sensitive to quick-killing analogues, confirming that the quick killing activity of these drugs was not directed at the apicoplast. Further, activity against the related apicoplast containing parasite Toxoplasma gondii and the gram-positive bacterium Streptococcus pneumoniae did not show improvement over azithromycin, highlighting the specific improvement in antimalarial quick-killing activity. Metabolomic profiling of parasites subjected to the most potent compound showed a build-up of non-haemoglobin derived peptides that was similar to chloroquine, while also exhibiting accumulation of haemoglobin-derived peptides that was absent for chloroquine treatment. DISCUSSION: The azithromycin analogues characterised in this study expand the structural diversity over pr
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- 2022
9. Multidrug-resistant Stenotrophomonas maltophilia in residential aged care facilities: An emerging threat.
- Author
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Sapula SA, Hart BJ, Siderius NL, Amsalu A, Blaikie JM, and Venter H
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- Humans, Genotype, Australia, Wastewater microbiology, Prevalence, Genetic Variation, Colistin pharmacology, Carbapenems pharmacology, Aged, Residential Facilities, Stenotrophomonas maltophilia drug effects, Stenotrophomonas maltophilia genetics, Stenotrophomonas maltophilia isolation & purification, Stenotrophomonas maltophilia classification, Drug Resistance, Multiple, Bacterial genetics, Microbial Sensitivity Tests, Anti-Bacterial Agents pharmacology, Gram-Negative Bacterial Infections microbiology, Gram-Negative Bacterial Infections epidemiology
- Abstract
Stenotrophomonas maltophilia is a multidrug-resistant (MDR), Gram-negative bacterium intrinsically resistant to beta-lactams, including last-resort carbapenems. As an opportunistic pathogen, it can cause serious healthcare-related infections. This study assesses the prevalence, resistance profiles, and genetic diversity of S. maltophilia isolated from residential aged care facilities (RACFs). RACFs are known for their overuse and often inappropriate use of antibiotics, creating a strong selective environment that favors the development of bacterial resistance. The study was conducted on 73 S. maltophilia isolates recovered from wastewater and facility swab samples obtained from three RACFs and a retirement village. Phenotypic and genotypic assessments of the isolates revealed high carbapenem resistance, exemplifying their intrinsic beta-lactam resistance. Alarmingly, 49.3% (36/73) of the isolates were non-wild type for colistin, with minimum inhibitory concentration values of > 4 mg/L, and 11.0% (8/73) were resistant to trimethoprim-sulfamethoxazole. No resistance mechanisms were detected for either antimicrobial. Genotypic assessment of known lineages revealed isolates clustering with Sm17 and Sm18, lineages not previously reported in Australia, suggesting the potential ongoing spread of MDR S. maltophilia. Lastly, although only a few isolates were biocide tolerant (2.7%, 2/73), their ability to grow in high concentrations (64 mg/L) of triclosan is concerning, as it may be selecting for their survival and continued dissemination., (© 2024 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)
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- 2024
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10. Resistome Analysis of Klebsiella pneumoniae Complex from Residential Aged Care Facilities Demonstrates Intra-facility Clonal Spread of Multidrug-Resistant Isolates.
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Blaikie JM, Sapula SA, Siderius NL, Hart BJ, Amsalu A, Leong LEX, Warner MS, and Venter H
- Abstract
Antimicrobial-resistant Klebsiella pneumoniae is one of the predominant pathogens in healthcare settings. However, the prevalence and resistome of this organism within residential aged care facilities (RACFs), which are potential hotspots for antimicrobial resistance, remain unexplored. Here, we provide a phenotypic and molecular characterization of antimicrobial-resistant K. pneumoniae isolated from RACFs. K. pneumoniae was isolated from urine, faecal and wastewater samples and facility swabs. The antimicrobial susceptibility profiles of all the isolates were determined and the genomic basis for resistance was explored with whole-genome sequencing on a subset of isolates. A total of 147 K. pneumoniae were isolated, displaying resistance against multiple antimicrobials. Genotypic analysis revealed the presence of beta-lactamases and the ciprofloxacin-resistance determinant QnrB4 but failed to confirm the basis for the observed cephalosporin resistance. Clonal spread of the multidrug-resistant, widely disseminated sequence types 323 and 661 was observed. This study was the first to examine the resistome of K. pneumoniae isolates from RACFs and demonstrated a complexity between genotypic and phenotypic antimicrobial resistance. The intra-facility dissemination and persistence of multidrug-resistant clones is concerning, given that residents are particularly vulnerable to antimicrobial resistant infections, and it highlights the need for continued surveillance and interventions to reduce the risk of outbreaks.
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- 2024
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11. Identification and evolution of ICE-PmuST394: a novel integrative conjugative element in Pasteurella multocida ST394.
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Roy Chowdhury P, Alhamami T, Venter H, Veltman T, Carr M, Mollinger J, Trott DJ, and Djordjevic SP
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- Animals, Cattle, Australia, Anti-Bacterial Agents pharmacology, Macrolides pharmacology, Pasteurella multocida genetics
- Abstract
Background: The emergence of macrolide and tetracycline resistance within Pasteurella multocida isolated from feedlot cattle and the dominance of ST394 in Australia was reported recently., Objectives: To establish the genetic context of the resistance genes in P. multocida 17BRD-035, the ST394 reference genome, and conduct a molecular risk assessment of their ability to disperse laterally., Methods: A bioinformatic analysis of the P. multocida 17BRD-035 genome was conducted to determine if integrative conjugative elements (ICEs) carrying resistance genes, which hamper antibiotic treatment options locally, are in circulation in Australian feedlots., Results: A novel element, ICE-PmuST394, was characterized in P. multocida 17BRD-035. It was also identified in three other isolates (two ST394s and a ST125) in Australia and is likely present in a genome representing P. multocida ST79 from the USA. ICE-PmuST394 houses a resistance module carrying two variants of the blaROB gene, blaROB-1 and blaROB-13, and the macrolide esterase gene, estT. The resistance gene combination on ICE-PmuST394 confers resistance to ampicillin and tilmicosin, but not to tulathromycin and tildipirosin. Our analysis suggests that ICE-PmuST394 is circulating both by clonal expansion and horizontal transfer but is currently restricted to a single feedlot in Australia., Conclusions: ICE-PmuST394 carries a limited number of unusual antimicrobial resistance genes but has hotspots that facilitate genomic recombination. The element is therefore amenable to hosting more resistance genes, and therefore its presence (or dispersal) should be regularly monitored. The element has a unique molecular marker, which could be exploited for genomic surveillance purposes locally and globally., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)
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- 2024
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12. Identification and characterization of CIM-1, a carbapenemase that adds to the family of resistance factors against last resort antibiotics.
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Wang Y, Sapula SA, Whittall JJ, Blaikie JM, Lomovskaya O, and Venter H
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- beta-Lactamases genetics, Bacterial Proteins genetics, Anti-Bacterial Agents pharmacology, R Factors
- Abstract
The increasing rate of carbapenem-resistant bacteria within healthcare environments is an issue of great concern that needs urgent attention. This resistance is driven by metallo-β-lactamases (MBLs), which can catalyse the hydrolysis of almost all clinically available β-lactams and are resistant to all the clinically utilized β-lactamase inhibitors. In this study, an uncharacterized MBL is identified in a multidrug resistant isolate of the opportunistic pathogen, Chryseobacterium indologenes. Sequence analysis predicts this MBL (CIM-1) to be a lipoprotein with an atypical lipobox. Characterization of CIM-1 reveals it to be a high-affinity carbapenemase with a broad spectrum of activity that includes all cephalosporins and carbapenems. Results also shown that CIM-1 is potentially a membrane-associated MBL with an uncharacterized lipobox. Using prediction tools, we also identify more potentially lipidated MBLs with non-canonical lipoboxes highlighting the necessity of further investigation of lipidated MBLs., (© 2024. The Author(s).)
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- 2024
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13. Targeting Iron - Respiratory Reciprocity Promotes Bacterial Death.
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Sharifian Gh M, Norouzi F, Sorci M, Zaid TS, Pier GB, Achimovich A, Ongwae GM, Liang B, Ryan M, Lemke M, Belfort G, Gadjeva M, Gahlmann A, Pires MM, Venter H, Harris TE, and Laurie GW
- Abstract
Discovering new bacterial signaling pathways offers unique antibiotic strategies. Here, through an unbiased resistance screen of 3,884 gene knockout strains, we uncovered a previously unknown non-lytic bactericidal mechanism that sequentially couples three transporters and downstream transcription to lethally suppress respiration of the highly virulent P. aeruginosa strain PA14 - one of three species on the WHO's 'Priority 1: Critical' list. By targeting outer membrane YaiW, cationic lacritin peptide 'N-104' translocates into the periplasm where it ligates outer loops 4 and 2 of the inner membrane transporters FeoB and PotH, respectively, to suppress both ferrous iron and polyamine uptake. This broadly shuts down transcription of many biofilm-associated genes, including ferrous iron-dependent TauD and ExbB1. The mechanism is innate to the surface of the eye and is enhanced by synergistic coupling with thrombin peptide GKY20. This is the first example of an inhibitor of multiple bacterial transporters., Competing Interests: DECLARATION OF INTERESTS GWL is cofounder and CSO of TearSolutions, Inc; and cofounder and CTO of IsletRegen, LLC. Other authors declare no competing interests.
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- 2024
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14. Orthogonal Reversed-Phase C 18 and Pentafluorophenyl HPLC Separation for Phytochemical Profiling of Serrulatanes in Eremophila denticulata .
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Zhao Y, Li T, Kjaerulff L, Venter H, Coriani S, Møller BL, Semple S, and Staerk D
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- Chromatography, High Pressure Liquid, Australia, Hypoglycemic Agents chemistry, Flavonoids, Phytochemicals, Plant Extracts chemistry, Scrophulariaceae chemistry
- Abstract
Serrulatanes constitute a class of unique diterpenoids derived from all- Z nerylneryl diphosphate rather than the conventional all- E diterpenoid precursor geranylgeranyl diphosphate and thus provide an intriguing expansion of the chemical space of plant specialized metabolites. Plants of the Australian Eremophila genus are rich sources of structurally diverse serrulatanes. Here, we report the identification of 15 hitherto undescribed serrulatanes (eremoculatanes A-N), together with 16 previously reported compounds, from the EtOAc extract of Eremophila denticulata leaves. Isolation was performed by a combined use of systematic HPLC-PDA-HRMS-based phytochemical profiling and orthogonal reversed-phase C
18 and pentafluorophenyl separations. Among the new compounds isolated, eremoculatane A contains a C12 backbone, for which the configuration was established by comparison of experimentally measured and theoretically calculated ECD spectra. The antihyperglycemic and antibacterial activities of the E. denticulata extract were investigated by high-resolution inhibition profiling, and they indicated that major constituents, mainly serrulatanes and flavonoids, contributed to the observed activity of the extract. One flavonoid, eupafolin ( 4 ), displayed moderate α-glucosidase inhibitory activity with an IC50 value of 41.3 μM, and four serrulatanes ( 8 , 9 , 19g , and 19j ) showed more than 50% PTP1B inhibition at 200 μM.- Published
- 2023
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15. The scope of antimicrobial resistance in residential aged care facilities determined through analysis of Escherichia coli and the total wastewater resistome.
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Sapula SA, Amsalu A, Whittall JJ, Hart BJ, Siderius NL, Nguyen L, Gerber C, Turnidge J, and Venter H
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- Humans, Aged, Anti-Bacterial Agents pharmacology, Wastewater, Drug Resistance, Bacterial, Drug Resistance, Multiple, Bacterial genetics, beta-Lactamases genetics, Microbial Sensitivity Tests, Escherichia coli, Escherichia coli Infections epidemiology, Escherichia coli Infections microbiology
- Abstract
Importance: Antimicrobial resistance (AMR) is a global threat that imposes a heavy burden on our health and economy. Residential aged care facilities (RACFs), where frequent inappropriate antibiotic use creates a selective environment that promotes the development of bacterial resistance, significantly contribute to this problem. We used wastewater-based epidemiology to provide a holistic whole-facility assessment and comparison of antimicrobial resistance in two RACFs and a retirement village. Resistant Escherichia coli , a common and oftentimes problematic pathogen within RACFs, was isolated from the wastewater, and the phenotypic and genotypic AMR was determined for all isolates. We observed a high prevalence of an international high-risk clone, carrying an extended-spectrum beta-lactamase in one facility. Analysis of the entire resistome also revealed a greater number of mobile resistance genes in this facility. Finally, both facilities displayed high fluoroquinolone resistance rates-a worrying trend seen globally despite measures in place aimed at limiting their use., Competing Interests: The authors declare no conflict of interest.
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- 2023
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16. Combined Structure- and Ligand-Based Approach for the Identification of Inhibitors of AcrAB-TolC in Escherichia coli .
- Author
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Pisoni LA, Semple SJ, Liu S, Sykes MJ, and Venter H
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- Ligands, Membrane Transport Proteins metabolism, Bacterial Outer Membrane Proteins metabolism, Multidrug Resistance-Associated Proteins genetics, Multidrug Resistance-Associated Proteins metabolism, Anti-Bacterial Agents chemistry, Carrier Proteins genetics, Carrier Proteins metabolism, Escherichia coli, Escherichia coli Proteins metabolism
- Abstract
The inhibition of efflux pumps is a promising approach to combating multidrug-resistant bacteria. We have developed a combined structure- and ligand-based model, using OpenEye software, for the identification of inhibitors of AcrB, the inner membrane protein component of the AcrAB-TolC efflux pump in Escherichia coli . From a database of 1391 FDA-approved drugs, 23 compounds were selected to test for efflux inhibition in E. coli . Seven compounds, including ivacaftor ( 25 ), butenafine ( 19 ), naftifine ( 27 ), pimozide ( 30 ), thioridazine ( 35 ), trifluoperazine ( 37 ), and meloxicam ( 26 ), enhanced the activity of at least one antimicrobial substrate and inhibited the efflux pump-mediated removal of the substrate Nile Red from cells. Ivacaftor ( 25 ) inhibited efflux dose dependently, had no effect on an E. coli strain with genomic deletion of the gene encoding AcrB, and did not damage the bacterial outer membrane. In the presence of a sub-minimum inhibitory concentration (MIC) of the outer membrane permeabilizer colistin, ivacaftor at 1 μg/mL reduced the MICs of erythromycin and minocycline by 4- to 8-fold. The identification of seven potential AcrB inhibitors shows the merits of a combined structure- and ligand-based approach to virtual screening.
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- 2023
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17. Oral administration of a 2-aminopyrimidine robenidine analogue (NCL195) significantly reduces Staphylococcus aureus infection and reduces Escherichia coli infection in combination with sub-inhibitory colistin concentrations in a bioluminescent mouse model.
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Nguyen HT, Venter H, Woolford L, Young KA, McCluskey A, Garg S, Sapula SS, Page SW, Ogunniyi AD, and Trott DJ
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- Mice, Animals, Colistin pharmacology, Colistin therapeutic use, Staphylococcus aureus, Escherichia coli, Robenidine therapeutic use, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Administration, Oral, Microbial Sensitivity Tests, Escherichia coli Infections microbiology, Staphylococcal Infections drug therapy, Peritonitis drug therapy, Sepsis drug therapy, Bacteremia drug therapy
- Abstract
We have previously reported promising in vivo activity of the first-generation 2-aminopyramidine robenidine analogue NCL195 against Gram-positive bacteria (GPB) when administered via the systemic route. In this study, we examined the efficacy of oral treatment with NCL195 (± low-dose colistin) in comparison to oral moxifloxacin in bioluminescent Staphylococcus aureus and Escherichia coli peritonitis-sepsis models. Four oral doses of 50 mg/kg NCL195, commencing immediately post-infection, were administered at 4 h intervals in the S. aureus peritonitis-sepsis model. We used a combination of four oral doses of 50 mg/kg NCL195 and four intraperitoneal doses of colistin at 0.125 mg/kg, 0.25 mg/kg, or 0.5 mg/kg in the E. coli peritonitis-sepsis model. Subsequently, the dose rates of four intraperitoneal doses of colistin were increased to 0.5 mg/kg, 1 mg/kg, or 2 mg/kg at 4 h intervals to treat a colistin-resistant E. coli infection. In the S. aureus infection model, oral treatment of mice with NCL195 resulted in significantly reduced S. aureus infection loads ( P < 0.01) and longer survival times ( P < 0.001) than vehicle-only treated mice. In the E. coli infection model, co-administration of NCL195 and graded doses of colistin resulted in a dose-dependent significant reduction in colistin-susceptible ( P < 0.01) or colistin-resistant ( P < 0.05) E. coli loads compared to treatment with colistin alone at similar concentrations. Our results confirm that NCL195 is a potential candidate for further preclinical development as a specific treatment for multidrug-resistant infections, either as a stand-alone antibiotic for GPB or in combination with sub-inhibitory concentrations of colistin for Gram-negative bacteria., Competing Interests: Stephen W. Page is a director of Neoculi Pty. Ltd. Darren J. Trott and Adam McCluskey have received research funding from Neoculi Pty. Ltd.
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- 2023
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18. Genomic profiling of Pasteurella multocida isolated from feedlot cases of bovine respiratory disease.
- Author
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Alhamami T, Roy Chowdhury P, Venter H, Veltman T, Truswell A, Abraham S, Sapula SA, Carr M, Djordjevic SP, and Trott DJ
- Subjects
- Cattle, Animals, Lipopolysaccharides, Phylogeny, Anti-Bacterial Agents pharmacology, Genomics, Macrolides, Victoria, Pasteurella multocida genetics, Cattle Diseases epidemiology, Respiratory Tract Diseases veterinary, Pasteurella Infections epidemiology, Pasteurella Infections veterinary
- Abstract
Pasteurella multocida causes a range of diseases in many host species throughout the world, including bovine respiratory disease (BRD) which is predominantly seen in feedlot cattle. This study assessed genetic diversity among 139 P. multocida isolates obtained from post-mortem lung swabs of BRD-affected feedlot cattle in four Australian states: New South Wales, Queensland, South Australia, and Victoria during 2014-2019. Whole-genome sequencing (WGS) was used to determine capsular serogroup, lipopolysaccharide genotypes, multi-locus sequence types and phylogenetic relationships. Two capsular types (A and D), with most isolates (132/139; 95%) belonging to type A; and three lipopolysaccharide (LPS) genotypes were identified (L1 [6/139; 4.3%], L3 [124/139; 89.2%] and L6 [9/139; 6.4%)]). Multi-locus sequence types (STs) ST9, ST13, ST17, ST20, ST36, ST50, ST58, ST79, ST124, ST125, ST132, ST167, ST185, ST327, ST394, and three novel STs [ST396, ST397, and ST398] were identified, with ST394 (59/139; 42.4%) and ST79 (44/139; 32%) the most prevalent in all four states. Isolates displaying phenotypic resistance to single, dual or multiple antibiotics (macrolide, tetracycline and aminopenicillins) were predominantly ST394 (23/139; 17%). Laterally mobile elements identified in the resistant ST394 isolates included small plasmids, encoding macrolide and/or tetracycline resistance, distributed in all states; and chromosomally located integrative conjugative elements (ICEs) (4 ST394 and 1 ST125) from the same Queensland feedlot. This study highlights the genomic diversity, epidemiological relationships and AMR associations in bovine P. multocida isolates from Australia and provides insight into the unique ST prevalence compared to other major beef-producing countries., Competing Interests: Declaration of Competing Interest I confirm that none of the authors of this paper has a financial or personal relationship with other people or organisations that could improperly influence or bias the content of this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)
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- 2023
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19. Polypharmacology-Labeled Molecular Networking: An Analytical Technology Workflow for Accelerated Identification of Multiple Bioactive Constituents in Complex Extracts.
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Zhao Y, Gericke O, Li T, Kjaerulff L, Kongstad KT, Heskes AM, Møller BL, Jørgensen FS, Venter H, Coriani S, Semple SJ, and Staerk D
- Subjects
- Polypharmacology, Workflow, Anti-Bacterial Agents pharmacology, Hypoglycemic Agents pharmacology, Hypoglycemic Agents chemistry, Plant Extracts pharmacology, Plant Extracts chemistry, Methicillin-Resistant Staphylococcus aureus
- Abstract
Discovery of sustainable and benign-by-design drugs to combat emerging health pandemics calls for new analytical technologies to explore the chemical and pharmacological properties of Nature's unique chemical space. Here, we present a new analytical technology workflow, polypharmacology-labeled molecular networking (PLMN), where merged positive and negative ionization tandem mass spectrometry-based molecular networking is linked with data from polypharmacological high-resolution inhibition profiling for easy and fast identification of individual bioactive constituents in complex extracts. The crude extract of Eremophila rugosa was subjected to PLMN analysis for the identification of antihyperglycemic and antibacterial constituents. Visually easy-interpretable polypharmacology scores and polypharmacology pie charts as well as microfractionation variation scores of each node in the molecular network provided direct information about each constituent's activity in the seven assays included in this proof-of-concept study. A total of 27 new non-canonical nerylneryl diphosphate-derived diterpenoids were identified. Serrulatane ferulate esters were shown to be associated with antihyperglycemic and antibacterial activities, including some showing synergistic activity with oxacillin in clinically relevant (epidemic) methicillin-resistant Staphylococcus aureus strains and some showing saddle-shaped binding to the active site of protein-tyrosine phosphatase 1B. PLMN is scalable in the number and types of assays included and thus holds potential for a paradigm shift toward polypharmacological natural-products-based drug discovery.
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- 2023
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20. Design and synthesis of benzochromene derivatives as AcrB inhibitors for the reversal of bacterial multidrug resistance.
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Guo T, Chen Y, Chen W, Semple SJ, Gu X, Polyak SW, Sun G, Venter H, and Ma S
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- Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents chemistry, Erythromycin pharmacology, Drug Resistance, Multiple, Multidrug Resistance-Associated Proteins, Drug Resistance, Multiple, Bacterial, Microbial Sensitivity Tests, Escherichia coli Proteins
- Abstract
A series of novel benzo[h]chromene compounds were designed, synthesized and evaluated for their biological activity as AcrB inhibitors. The compounds were assessed for their ability to potentiate the effect of antibiotics. Compounds with antibiotic-potentiating effects were then evaluated for inhibition of Nile Red efflux, and for off-target effects including activity on the outer and inner bacterial membranes and toxicity. Six compounds were identified to reduce the MIC values of at least one of the tested antibiotics by at least 4-fold, and further reduced the MICs in the presence of a membrane permeabilizer. The identified compounds were also able to inhibit Nile Red efflux at concentrations between 50 μM and 200 μM. The compounds did not disrupt the bacterial outer membrane nor display toxicity in a nematode model (Caenorhabditis elegans). The 4-methoxyphenoxy)propoxy derivative compound G6 possessed the most potent antibacterial potentiation with erythromycin by 8-fold even without the presence of a membrane permeabilizer. Furthermore, H6, G6, G10 and G11 completely abolished the Nile Red efflux at a concentration of 50 μM. The 3,4-dihydro-2H-benzo[h]chromen-5-yl)(morpholino)methanone core appears to be a promising chemical skeleton to be further studied in the discovery of more putative AcrB inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
- Published
- 2023
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21. Targeting malaria parasites with novel derivatives of azithromycin.
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Burns AL, Sleebs BE, Gancheva M, McLean KT, Siddiqui G, Venter H, Beeson JG, O'Handley R, Creek DJ, Ma S, Frölich S, Goodman CD, McFadden GI, and Wilson DW
- Subjects
- Animals, Humans, Azithromycin pharmacology, Plasmodium falciparum, Chloroquine pharmacology, Chloroquine therapeutic use, Antimalarials pharmacology, Parasites, Malaria, Falciparum drug therapy, Malaria, Falciparum parasitology, Malaria drug therapy, Malaria parasitology
- Abstract
Introduction: The spread of artemisinin resistant Plasmodium falciparum parasites is of global concern and highlights the need to identify new antimalarials for future treatments. Azithromycin, a macrolide antibiotic used clinically against malaria, kills parasites via two mechanisms: 'delayed death' by inhibiting the bacterium-like ribosomes of the apicoplast, and 'quick-killing' that kills rapidly across the entire blood stage development., Methods: Here, 22 azithromycin analogues were explored for delayed death and quick-killing activities against P. falciparum (the most virulent human malaria) and P. knowlesi (a monkey parasite that frequently infects humans)., Results: Seventeen analogues showed improved quick-killing against both Plasmodium species, with up to 38 to 20-fold higher potency over azithromycin after less than 48 or 28 hours of treatment for P. falciparum and P. knowlesi , respectively. Quick-killing analogues maintained activity throughout the blood stage lifecycle, including ring stages of P. falciparum parasites (<12 hrs treatment) and were >5-fold more selective against P. falciparum than human cells. Isopentenyl pyrophosphate supplemented parasites that lacked an apicoplast were equally sensitive to quick-killing analogues, confirming that the quick killing activity of these drugs was not directed at the apicoplast. Further, activity against the related apicoplast containing parasite Toxoplasma gondii and the gram-positive bacterium Streptococcus pneumoniae did not show improvement over azithromycin, highlighting the specific improvement in antimalarial quick-killing activity. Metabolomic profiling of parasites subjected to the most potent compound showed a build-up of non-haemoglobin derived peptides that was similar to chloroquine, while also exhibiting accumulation of haemoglobin-derived peptides that was absent for chloroquine treatment., Discussion: The azithromycin analogues characterised in this study expand the structural diversity over previously reported quick-killing compounds and provide new starting points to develop azithromycin analogues with quick-killing antimalarial activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Burns, Sleebs, Gancheva, McLean, Siddiqui, Venter, Beeson, O’Handley, Creek, Ma, Frölich, Goodman, McFadden and Wilson.)
- Published
- 2022
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22. In Vitro Activity of Robenidine Analogues NCL259 and NCL265 against Gram-Negative Pathogens.
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Pi H, Venter H, Russell CC, Young KA, McCluskey A, Page SW, Ogunniyi AD, and Trott DJ
- Abstract
Multidrug-resistant (MDR) Gram-negative pathogens, especially Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Enterobacter spp., are recognized by the World Health Organization as the most critical priority pathogens in urgent need of drug development. In this study, the in vitro antimicrobial activity of robenidine analogues NCL259 and NCL265 was tested against key human and animal Gram-negative clinical isolates and reference strains. NCL259 and NCL265 demonstrated moderate antimicrobial activity against these Gram-negative priority pathogens with NCL265 consistently more active, achieving lower minimum inhibitory concentrations (MICs) in the range of 2−16 µg/mL. When used in combination with sub-inhibitory concentrations of polymyxin B to permeabilize the outer membrane, NCL259 and NCL265 elicited a synergistic or additive activity against the reference strains tested, reducing the MIC of NCL259 by 8- to 256- fold and the MIC of NCL265 by 4- to 256- fold. A small minority of Klebsiella spp. isolates (three) were resistant to both NCL259 and NCL265 with MICs > 256 µg/mL. This resistance was completely reversed in the presence of the efflux pump inhibitor phenylalanine-arginine-beta-naphthylamide (PAβN) to yield MIC values of 8−16 µg/mL and 2−4 µg/mL for NCL259 and NCL256, respectively. When NCL259 and NCL265 were tested against wild-type E. coli isolate BW 25113 and its isogenic multidrug efflux pump subunit AcrB deletion mutant (∆AcrB), the MIC of both compounds against the mutant ∆AcrB isolate was reduced 16-fold compared to the wild-type parent, indicating a significant role for the AcrAB-TolC efflux pump from Enterobacterales in imparting resistance to these robenidine analogues. In vitro cytotoxicity testing revealed that NCL259 and NCL265 had much higher levels of toxicity to a range of human cell lines compared to the parent robenidine, thus precluding their further development as novel antibiotics against Gram-negative pathogens.
- Published
- 2022
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23. Bioactivity-guided isolation of compounds from Sophora flavescens with antibacterial activity against Acinetobacter baumannii .
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Li P, Chai WC, Wang ZY, Tang KJ, Chen JY, Venter H, Semple SJ, and Xiang L
- Subjects
- Anti-Bacterial Agents analysis, Anti-Bacterial Agents pharmacology, Flavonoids chemistry, Plant Extracts analysis, Plant Roots chemistry, Acinetobacter baumannii, Sophora chemistry
- Abstract
Bioactivity-guided fraction of an extract of Sophora flavescens to identify antibacterial compounds against Acinetobacter baumannii , led to the isolation of two new compounds, (2″ R )-5-methoxy-7-hydroxy-8-lavandulylchromone (13) and (2 S , βS )-(-)-sophobiflavonoid CE (19), and 18 known flavonoids, (6a R ,11a R )-(-)-maackiain (1), (2 S )-(-)-8-prenylnaringenin (2), (2 S )-(-)-exiguaflavanone K (3), (2 S )-(-)-sophoraflavanone G (4), (2 S )-(-)-leachianone A (5), (2 S )-(-)-kushenol E (6), (2 S )-(-)-leachianone G (7), (±)-kushenol F (8), (2 S )-(-)-kurarinone (9), (2 S )-(-)-kurarinol (10), (2 R ,3 R )- (+)-3,7,4'-trihydroxy-5-methoxy-8-prenylflavanone (11), (2 S )-(-)-isoxanthohumol (12), (2 S )-(-)-2'-methoxykurarinone (14), (2 R ,3 R )-(+)-kushenol I (15), calycosin (16), kuraridin (17), (2 S )-(-)-kushenol A (18), and trifolirhizin (20). Their structures were elucidated based on NMR, MS, and CD spectroscopic analysis. Among them, 1 , 2 , 5 , and 15 exerted modest antibacterial activity against A. baumannii , with MIC
95 of 128-256 μg/mL for 2 and 256-512 μg/mL for 1 , 5 and 15 .- Published
- 2022
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24. Cinnamaldehyde derivatives act as antimicrobial agents against Acinetobacter baumannii through the inhibition of cell division.
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Chai WC, Whittall JJ, Polyak SW, Foo K, Li X, Dutschke CJ, Ogunniyi AD, Ma S, Sykes MJ, Semple SJ, and Venter H
- Abstract
Acinetobacter baumannii is a pathogen with high intrinsic antimicrobial resistance while multidrug resistant (MDR) and extensively drug resistant (XDR) strains of this pathogen are emerging. Treatment options for infections by these strains are very limited, hence new therapies are urgently needed. The bacterial cell division protein, FtsZ, is a promising drug target for the development of novel antimicrobial agents. We have previously reported limited activity of cinnamaldehyde analogs against Escherichia coli . In this study, we have determined the antimicrobial activity of six cinnamaldehyde analogs for antimicrobial activity against A. baumannii . Microscopic analysis was performed to determine if the compounds inhibit cell division. The on-target effect of the compounds was assessed by analyzing their effect on polymerization and on the GTPase activity of purified FtsZ from A. baumannii . In silico docking was used to assess the binding of cinnamaldehyde analogs. Finally, in vivo and in vitro safety assays were performed. All six compounds displayed antibacterial activity against the critical priority pathogen A. baumannii , with 4-bromophenyl-substituted 4 displaying the most potent antimicrobial activity (MIC 32 μg/mL). Bioactivity was significantly increased in the presence of an efflux pump inhibitor for A. baumannii ATCC 19606 (up to 32-fold) and significantly, for extensively drug resistant UW 5075 (greater than 4-fold), suggesting that efflux contributes to the intrinsic resistance of A. baumannii against these agents. The compounds inhibited cell division in A. baumannii as observed by the elongated phenotype and targeted the FtsZ protein as seen from the inhibition of polymerization and GTPase activity. In silico docking predicted that the compounds bind in the interdomain cleft adjacent to the H7 core helix. Di-chlorinated 6 was devoid of hemolytic activity and cytotoxicity against mammalian cells in vitro , as well as adverse activity in a Caenorhabditis elegans nematode model in vivo . Together, these findings present halogenated analogs 4 and 6 as promising candidates for further development as antimicrobial agents aimed at combating A. baumannii . This is also the first report of FtsZ-targeting compounds with activity against an XDR A. baumannii strain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chai, Whittall, Polyak, Foo, Li, Dutschke, Ogunniyi, Ma, Sykes, Semple and Venter.)
- Published
- 2022
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25. Antimicrobial susceptibility and genomic analysis of Histophilus somni isolated from cases of bovine respiratory disease in Autralian feedlot cattle.
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Alhamami T, Low WY, Ren Y, Taylor K, Khazandi M, Veltman T, Venter H, Carr M, Turni C, Abraham S, and Trott DJ
- Subjects
- Animals, Anti-Bacterial Agents pharmacology, Australia epidemiology, Cattle, Genomics, Horses, Phylogeny, Respiratory System, Cattle Diseases epidemiology, Horse Diseases, Pasteurellaceae genetics, Respiratory Tract Diseases veterinary
- Abstract
Histophilus somni is a prevalent commensal organism of the upper respiratory tract of cattle and a major causative agent of bovine respiratory disease (BRD) and other syndromes including myocarditis and infectious thromboembolic meningoencephalitis. This study investigated the antimicrobial susceptibility and phylogenetic relationships of H. somni isolates obtained from lung, heart, and other tissues at post-mortem as well as nasal mucosa swabs from cases of BRD in Australian feedlots (2004-2019). Broth microdilution Minimal Inhibitory Concentration (MIC) assays were determined for 19 antimicrobials using three different media (CLSI approved Veterinary Fastidious Medium [VFM], Mueller-Hinton fastidious broth medium supplemented with yeast extract [MHF-Y] and Columbia Broth [CB] supplemented with 5% lysed horse blood). For all antimicrobials, MICs obtained using CB medium were identical or within 1 dilution step of the MICs obtained for VFM and MHF-Y media. Therefore, CB may be a suitable medium for H. somni antimicrobial susceptibility testing similar to MHF-Y medium. None of the 70 Australian H. somni isolates exhibited resistance to antimicrobials with CLSI breakpoints including those commonly used in the treatment of BRD in Australia (first-line tetracyclines [chlortetracycline and oxytetracycline], second-line macrolides [tulathromycin], and third-line extended-spectrum cephalosporin [ceftiofur]). Whole-genome sequence analysis of 65 H. somni isolates for genomic single nucleotide polymorphism differences identified four phylogenetic clusters, each containing isolates from different Australian states, feedlots and tissue sources that clustered together. These findings demonstrate limited genetic diversity and the absence of significant antimicrobial resistance among Australian isolates of H. somni isolated from feedlot cattle., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2022
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26. Correction: Alhamami et al. First Emergence of Resistance to Macrolides and Tetracycline Identified in Mannheimia haemolytica and Pasteurella multocida Isolates from Beef Feedlots in Australia. Microorganisms 2021, 9 , 1322.
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Alhamami T, Roy Chowdhury P, Gomes N, Carr M, Veltman T, Khazandi M, Mollinger J, Deutscher AT, Turni C, Mahdi L, Venter H, Abraham S, Djordjevic SP, and Trott DJ
- Abstract
The authors wish to make the following corrections to this paper [...].
- Published
- 2022
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27. The Structural and Functional Study of Efflux Pumps Belonging to the RND Transporters Family from Gram-Negative Bacteria.
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Vargiu AV, Phan G, Venter H, and Broutin I
- Abstract
Antimicrobial-resistant bacterial infections are a major and costly public health concern [...].
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- 2022
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28. Complete Genome Sequence of Pasteurella multocida Sequence Type 394, Isolated from a Case of Bovine Respiratory Disease in Australia.
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Roy Chowdhury P, Alhamami T, Venter H, Veltman T, Carr M, Mollinger J, Trott DJ, and Djordjevic SP
- Abstract
Here, we present the completely closed genome sequence of Pasteurella multocida 17BRD-035, a bovine respiratory disease (BRD) pathogen from Queensland, Australia, with genes that confer resistance to β-lactams, tilmicosin, and tetracycline. It consists of a single 2,624,884-bp chromosome and an average GC content of 40.23% and belongs to the newly described Rural Industries Research and Development Corporation (RIRDC) sequence type 394.
- Published
- 2022
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29. Impact of a Novel Anticoccidial Analogue on Systemic Staphylococcus aureus Infection in a Bioluminescent Mouse Model.
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Nguyen HT, Venter H, Woolford L, Young K, McCluskey A, Garg S, Page SW, Trott DJ, and Ogunniyi AD
- Abstract
In this study, we investigated the potential of an analogue of robenidine (NCL179) to expand its chemical diversity for the treatment of multidrug-resistant (MDR) bacterial infections. We show that NCL179 exhibits potent bactericidal activity, returning minimum inhibitory concentration/minimum bactericidal concentrations (MICs/MBCs) of 1-2 µg/mL against methicillin-resistant Staphylococcus aureus , MICs/MBCs of 1-2 µg/mL against methicillin-resistant S. pseudintermedius and MICs/MBCs of 2-4 µg/mL against vancomycin-resistant enterococci. NCL179 showed synergistic activity against clinical isolates and reference strains of Acinetobacter baumannii , Escherichia coli , Klebsiella pneumoniae and Pseudomonas aeruginosa in the presence of sub-inhibitory concentrations of colistin, whereas NCL179 alone had no activity. Mice given oral NCL179 at 10 mg/kg and 50 mg/kg (4 × doses, 4 h apart) showed no adverse clinical effects and no observable histological effects in any of the organs examined. In a bioluminescent S. aureus sepsis challenge model, mice that received four oral doses of NCL179 at 50 mg/kg at 4 h intervals exhibited significantly reduced bacterial loads, longer survival times and higher overall survival rates than the vehicle-only treated mice. These results support NCL179 as a valid candidate for further development to treat MDR bacterial infections as a stand-alone antibiotic or in combination with existing antibiotic classes.
- Published
- 2022
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30. Worldwide distribution and environmental origin of the Adelaide imipenemase (AIM-1), a potent carbapenemase in Pseudomonas aeruginosa .
- Author
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Amsalu A, Sapula SA, Whittall JJ, Hart BJ, Bell JM, Turnidge J, and Venter H
- Subjects
- Amino Acid Sequence, Animals, Asia, Europe, High-Throughput Nucleotide Sequencing, Humans, Microbial Sensitivity Tests, North America, Phylogeny, Phylogeography, Pseudomonas aeruginosa drug effects, Pseudomonas aeruginosa genetics, Wastewater microbiology, Bacterial Proteins genetics, Carbapenems pharmacology, Drug Resistance, Bacterial, Pseudomonas aeruginosa classification, Whole Genome Sequencing methods, beta-Lactamases genetics
- Abstract
Carbapenems are potent broad-spectrum β-lactam antibiotics reserved for the treatment of serious infections caused by multidrug-resistant bacteria such as Pseudomonas aeruginosa . The surge in P. aeruginosa resistant to carbapenems is an urgent threat, as very few treatment options remain. Resistance to carbapenems is predominantly due to the presence of carbapenemase enzymes. The assessment of 147 P . aeruginosa isolates revealed that 32 isolates were carbapenem non-wild-type. These isolates were screened for carbapenem resistance genes using PCR. One isolate from wastewater contained the Adelaide imipenemase gene ( bla
AIM-1 ) and was compared phenotypically with a highly carbapenem-resistant clinical isolate containing the blaAIM-1 gene. A further investigation of wastewater samples from various local healthcare and non-healthcare sources as well as river water, using probe-based qPCR, revealed the presence of the blaAIM-1 gene in all the samples analysed. The widespread occurrence of blaAIM-1 throughout Adelaide hinted at the possibility of more generally extensive spread of this gene than originally thought. A blast search revealed the presence of the blaAIM-1 gene in Asia, North America and Europe. To elucidate the identity of the organism(s) carrying the blaAIM-1 gene, shotgun metagenomic sequencing was conducted on three wastewater samples from different locations. Comparison of these nucleotide sequences with a whole-genome sequence of a P. aeruginosa isolate revealed that, unlike the genetic environment and arrangement in P. aeruginosa , the blaAIM-1 gene was not carried as part of any mobile genetic elements. A phylogenetic tree constructed with the deduced amino acid sequences of AIM-1 suggested that the potential origin of the blaAIM-1 gene in P. aeruginosa might be the non-pathogenic environmental organism, Pseudoxanthomonas mexicana .- Published
- 2021
- Full Text
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