Bacterial adherence to host tissues: a very sticky problem.
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Animals↗
Biomedical subjects
Andrew S Waller
Publications and source records attributed to Andrew S Waller.
Getting a grip on strangles: recent progress towards improved diagnostics and vaccines.
'Strangles', caused by infection with the bacterium Streptococcus equi, remains one of the most commonly diagnosed and important infectious diseases of horses world-wide. This review discusses the diagnosis and pathogenesis of strangles with particular attention to the significance of persistent infections in disease transmission and the rapid progress now being made towards the development of effective preventative vaccines. It is now possible combine recent sequence data from the N-terminal region of the SeM protein and reassign the SeM alleles using the on-line database http://pubmlst.org/szooepidemicus/seM/. Hypotheses concerning the origin of this variation and the potential for its exploitation for the epidemiological analysis of outbreaks are proposed. Advances in understanding of the molecular evolution of S. equi highlight the role played by phage-mediated acquisition of virulence factors and suggest new avenues for prophylactic intervention.
Animals↗
Sequence variation of the SeM gene of Streptococcus equi allows discrimination of the source of strangles outbreaks.
Improved understanding of the epidemiology of Streptococcus equi transmission requires sensitive and portable subtyping methods that can rationally discriminate between strains. S. equi is highly homogeneous and cannot be distinguished by multilocus enzyme electrophoretic or multilocus sequence-typing methods that utilize housekeeping genes. However, on sequence analysis of the N-terminal region of the SeM genes of 60 S. equi isolates from 27 strangles outbreaks, we identified 21 DNA codon changes. These resulted in the nonsynonymous substitution of 18 amino acids and allowed the assignment of S. equi strains to 15 distinct subtypes. Our data suggest the presence of multiple epitopes across this region that are subjected to selective immune pressure (nonsynonymous-synonymous substitution rate [d(N)/d(S)] ratio = 3.054), particularly during the establishment of long-term S. equi infection. We further report the application of SeM gene subtyping as a method to investigate potential cases of disease related to administration of a live attenuated S. equi vaccine. SeM gene subtyping successfully differentiated between the vaccine strain and field strains of S. equi responsible for concurrent disease. These results were confirmed by the development and application of a PCR diagnostic test, which identifies the aroA partial gene deletion present in the Equilis StrepE vaccine strain. Although the vaccine strain was found to be responsible for injection site lesions, all seven outbreaks of strangles investigated in recently vaccinated horses were found to be due to concurrent infection with wild-type S. equi and not due to reversion of the vaccine strain.
Amino Acid Sequence↗
Novel approaches to antimicrobial therapy: peptide deformylase.
Peptide deformylase (PDF) represents one of the most exciting new targets for the development of novel antimicrobial chemotherapies. PDF is an essential bacterial metalloenzyme that deformylates the N-formylmethionine of newly synthesized bacterial polypeptides. Recent progress in understanding the structure and function of PDF has greatly facilitated the drug discovery process. In this article, the potential of PDF as an antimicrobial target is reviewed, and progress in the development of PDF inhibitors (PDFIs) is highlighted. Several structural classes of compounds have been reported as inhibitors of PDF. However, the real challenge has been in obtaining molecules with potent in vivo antibacterial activity against a range of drug-resistant pathogens. One of the more encouraging compounds reported, BB-83698 (British Biotech plc/Genesoft Inc), has shown in vivo efficacy against Streptococcus pneumoniae in both mouse thigh and lung infection models at doses equivalent to existing therapies. The published data suggest that PDFIs are a promising new class of antimicrobial agent best suited to treat respiratory tract infections (RTIs), but with the potential for activity against a variety of other pathogens. It is anticipated that the first PDFI targeting RTIs will enter the clinic soon.
Amidohydrolases↗