ORCID Profile
0000-0002-5878-8385
Current Organisation
University of South Australia
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Publisher: Public Library of Science (PLoS)
Date: 05-11-2015
Publisher: American Association for the Advancement of Science (AAAS)
Date: 14-09-2022
DOI: 10.1126/SCITRANSLMED.ABJ2381
Abstract: Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria ( Staphylococcus aureus and Streptococcus pneumoniae ) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC 90 ≤ 0.06 μg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae , as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.
Publisher: Elsevier BV
Date: 07-2023
Publisher: Public Library of Science (PLoS)
Date: 11-03-2013
Publisher: MDPI AG
Date: 17-06-2021
DOI: 10.3390/MICROORGANISMS9061322
Abstract: Bovine respiratory disease (BRD) causes high morbidity and mortality in beef cattle worldwide. Antimicrobial resistance (AMR) monitoring of BRD pathogens is critical to promote appropriate antimicrobial stewardship in veterinary medicine for optimal treatment and control. Here, the susceptibility of Mannheimia haemolytica and Pasteurella multicoda isolates obtained from BRD clinical cases (deep lung swabs at post-mortem) among feedlots in four Australian states (2014–2019) was determined for 19 antimicrobial agents. The M. haemolytica isolates were pan-susceptible to all tested agents apart from a single macrolide-resistant isolate (1/88 1.1%) from New South Wales (NSW). Much higher frequencies of P. multocida isolates were resistant to tetracycline (18/140 12.9%), tilmicosin (19/140 13.6%), tulathromycin/gamithromycin (17/140 12.1%), and icillin enicillin (6/140 4.6%). Five P. multocida isolates (3.6%), all obtained from NSW in 2019, exhibited dual resistance to macrolides and tetracycline, and a further two Queensland isolates from 2019 (1.4%) exhibited a multidrug-resistant phenotype to icillin enicillin, tetracycline, and tilmicosin. Random- lified polymorphic DNA (RAPD) typing identified a high degree of genetic homogeneity among the M. haemolytica isolates, whereas P. multocida isolates were more heterogeneous. Illumina whole genome sequencing identified the genes msr(E) and mph(E)encoding macrolide resistance, tet(R)-tet(H) or tet(Y) encoding tetracycline resistance, and blaROB-1 encoding icillin enicillin resistance in all isolates exhibiting a corresponding resistant phenotype. The exception was the tilmicosin-resistant, tulathromycin/gamithromycin-susceptible phenotype identified in two Queensland isolates, the genetic basis of which could not be determined. These results confirm the first emergence of AMR in M. haemolytica and P. multocida from BRD cases in Australia, which should be closely monitored.
Publisher: Elsevier BV
Date: 04-2017
Publisher: American Society for Microbiology
Date: 03-2016
DOI: 10.1128/IAI.01454-15
Abstract: Streptococcus pneumoniae is the leading infectious cause of death in children in the world. However, the mechanisms that drive the progression from asymptomatic colonization to disease are poorly understood. Two virulence-associated genomic accessory regions (ARs) were deleted in a highly virulent serotype 1 clinical isolate (strain 4496) and examined for their contribution to pathogenesis. Deletion of a prophage encoding a platelet-binding protein (PblB) resulted in reduced adherence, biofilm formation, reduced initial infection within the lungs, and a reduction in the number of circulating platelets in infected mice. However, the region's overall contribution to the survival of mice was not significant. In contrast, deletion of the variable region of pneumococcal pathogenicity island 1 (vPPI1) was also responsible for a reduction in adherence and biofilm formation but also reduced survival and invasion of the pleural cavity, blood, and lungs. While the 4496ΔPPI1 strain induced higher expression of the genes encoding interleukin-10 (IL-10) and CD11b in the lungs of challenged mice than the wild-type strain, very few other genes exhibited altered expression. Moreover, while the level of IL-10 protein was increased in the lungs of 4496ΔPPI1 mutant-infected mice compared to strain 4496-infected mice, the levels of gamma interferon (IFN-γ), CXCL10, CCL2, and CCL4 were not different in the two groups. However, the 4496ΔPPI1 mutant was found to be more susceptible than the wild type to phagocytic killing by a macrophage-like cell line. Therefore, our data suggest that vPPI1 may be a major contributing factor to the heightened virulence of certain serotype 1 strains, possibly by influencing resistance to phagocytic killing.
Publisher: Public Library of Science (PLoS)
Date: 13-08-2013
Publisher: American Society for Microbiology
Date: 02-2008
DOI: 10.1128/IAI.01161-07
Abstract: Pneumococcal disease continues to account for significant morbidity and mortality worldwide. For the development of novel prophylactic and therapeutic strategies against the disease spectrum, a complete understanding of pneumococcal behavior in vivo is necessary. We evaluated the expression patterns of the proven and putative virulence factor genes adcR , cbpA , cbpD , cbpG , cpsA , nanA , pcpA , piaA , ply , psaA , pspA , and spxB after intranasal infection of CD1 mice with serotype 2, 4, and 6A pneumococci by real-time reverse transcription-PCR. Simultaneous gene expression patterns of selected host immunomodulatory molecules, CCL2, CCL5, CD54, CXCL2, interleukin-6, and tomor necrosis factor alpha, were also investigated. We show that pneumococcal virulence genes are differentially expressed in vivo, with some genes demonstrating niche- and serotype-specific differential expression. The in vivo expression patterns could not be attributed to in vitro differences in expression of the genes in transparent and opaque variants of the three strains. The host molecules were significantly upregulated, especially in the lungs, blood, and brains of mice. The pneumococcal-gene expression patterns support their ascribed roles in pathogenesis, providing insight into which protein combinations might be more appropriate as vaccine antigens against invasive disease. This is the first simultaneous comparison of bacterial- and host gene expression in the same animal during pathogenesis. The strategy provides a platform for prospective evaluation of interaction kinetics between invading pneumococci and human patients in culture-positive cases and should be feasible in other infection models.
Publisher: Springer Science and Business Media LLC
Date: 19-11-2009
Publisher: American Society for Microbiology
Date: 09-2010
DOI: 10.1128/JB.00064-10
Abstract: The importance of Mn 2+ for pneumococcal physiology and virulence has been studied extensively. However, the specific cellular role(s) for which Mn 2+ is required are yet to be fully elucidated. Here, we analyzed the effect of Mn 2+ limitation on the transcriptome and proteome of Streptococcus pneumoniae D39. This was carried out by comparing a deletion mutant lacking the solute binding protein of the high-affinity Mn 2+ transporter, pneumococcal surface antigen A (PsaA), with its isogenic wild-type counterpart. We provide clear evidence for the Mn 2+ -dependent regulation of the expression of oxidative-stress-response enzymes SpxB and Mn 2+ -SodA and virulence-associated genes pcpA and prtA . We also demonstrate the upregulation of at least one oxidative- and nitrosative-stress-response gene cluster, comprising adhC , nmlR , and czcD , in response to Mn 2+ stress. A significant increase in 6-phosphogluconate dehydrogenase activity in the psaA mutant grown under Mn 2+ -replete conditions and upregulation of an oligopeptide ABC permease (AppDCBA) were also observed. Together, the results of transcriptomic and proteomic analyses provided evidence for Mn 2+ having a central role in activating or stimulating enzymes involved in central carbon and general metabolism. Our results also highlight the importance of high-affinity Mn 2+ transport by PsaA in pneumococcal competence, physiology, and metabolism and elucidate mechanisms underlying the response to Mn 2+ stress.
Publisher: American Society for Clinical Investigation
Date: 06-2012
DOI: 10.1172/JCI45850
Publisher: American Society for Microbiology
Date: 09-2012
DOI: 10.1128/IAI.00295-12
Abstract: Streptococcus pneumoniae (the pneumococcus) continues to be responsible for a high level of global morbidity and mortality resulting from pneumonia, bacteremia, meningitis, and otitis media. Here we have used a novel technique involving niche-specific, genome-wide in vivo transcriptomic analyses to identify genes upregulated in distinct niches during pathogenesis after intranasal infection of mice with serotype 4 or 6A pneumococci. The analyses yielded 28 common, significantly upregulated genes in the lungs relative to those in the nasopharynx and 25 significantly upregulated genes in the blood relative to those in the lungs in both strains, some of which were previously unrecognized. The role of five upregulated genes from either the lungs or the blood in pneumococcal pathogenesis and virulence was then evaluated by targeted mutagenesis. One of the mutants (Δ malX ) was significantly attenuated for virulence in the lungs, two (Δ aliA and Δ ilvH ) were significantly attenuated for virulence in the blood relative to the wild type, and two others (Δ cbiO and Δ piuA ) were completely avirulent in a mouse intranasal challenge model. We also show that the products of aliA , malX , and piuA are promising candidates for incorporation into multicomponent protein-based pneumococcal vaccines currently under development. Importantly, we suggest that this new approach is a viable complement to existing strategies for the discovery of genes critical to the distinct stages of invasive pneumococcal disease and potentially has broad application for novel protein antigen discovery in other pathogens such as S. pyogenes , Haemophilus influenzae type b, and Neisseria meningitidis .
Publisher: Wiley
Date: 29-10-2009
DOI: 10.1096/FJ.08-119537
Abstract: The pneumococcal histidine triad (Pht) proteins are a recently recognized family of surface proteins, comprising 4 members: PhtA, PhtB, PhtD, and PhtE. They are being promoted for inclusion in a multicomponent pneumococcal protein vaccine currently under development, but to date, their biological functions and their relative contributions to pathogenesis have not been clarified. In this study, the involvement of these proteins in pneumococcal virulence was investigated in murine models of sepsis and pneumonia by using defined, nonpolar mutants of the respective genes in Streptococcus pneumoniae D39. In either challenge model, mutagenesis of all 4 genes was required to completely abolish virulence relative to the wild-type, suggesting significant functional redundancy among Pht proteins. The in vivo expression of pht genes was significantly up-regulated in the nasopharynx and lungs compared with blood. We provide unequivocal molecular evidence for Zn(2+)-dependent, AdcR-mediated, regulation of pht gene expression by real-time reverse transcriptase-polymerase chain reaction, Western blotting, and electrophoretic mobility-shift assays. We also present the first direct evidence for the biological function of this protein family by demonstrating that Pht proteins are required for inhibition of complement deposition on the pneumococcal surface through the recruitment of complement factor H.
Publisher: American Society for Microbiology
Date: 31-08-2022
Abstract: Determining the antibiotic sensitivity of disease-causing microorganisms is a fundamental process in a clinical microbiology laboratory. With the continued use of antibiotics, the emergence of antibiotic resistance has become a significant health issue.
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.VETMIC.2018.08.004
Abstract: Spotty Liver Disease is an acute infectious disease of layer chickens that was likely first described in the USA and Canada in the 1950s and 1960's. The disease occurs almost exclusively in barn and free-range production systems. Outbreaks usually, but not exclusively occur in young layers (≅25 weeks) at peak of lay. Indicators of SLD include an acute drop in egg production of up to 35%, together with increased mortality of up to 15%. A presumptive diagnosis at post mortem is made with the detection of characteristic small yellow-white necrotic hepatic lesions, together with a fibrinous peri-hepatitis, excess pericardial and peritoneal fluid, and usually enteritis with diarrhoea. Histopathology reveals a multifocal acute hepatocellular necrosis with fibrin and occasional haemorrhage. Control measures trialled include use of antibiotics, improved biosecurity and hygiene, as well as management practices directed at reducing stress in flocks. However, none other than treatment with antibiotics has been consistently effective which suggested a bacterial aetiology. In 2015, a novel fastidious thermophilic, microaerobic c ylobacter was isolated from symptomatic SLD flocks in the UK. Subsequently, an Australian group isolated and further characterised a genetically similar bacterium and named it C ylobacter hepaticus. The bacterium can be cultured from the liver and bile of infected birds, although recovery from non-sterile organs such as the caecum and duodenum remains elusive. Consequently, the route of transmission remains unconfirmed, although molecular detection by PCR of C. hepaticus DNA in the gastrointestinal tract and faeces of SLD infected birds is highly suggestive of a faecal-oral route.
Publisher: Springer Science and Business Media LLC
Date: 08-09-2014
Publisher: Public Library of Science (PLoS)
Date: 26-10-2017
Publisher: MDPI AG
Date: 15-04-2022
DOI: 10.3390/MICROORGANISMS10040825
Abstract: The authors wish to make the following corrections to this paper [...]
Publisher: Public Library of Science (PLoS)
Date: 17-04-2015
No related grants have been discovered for Layla Mahdi.