Engineering microbes for targeted strikes against human pathogens

Lack of pathogen specificity in antimicrobial therapy causes non-discriminant microbial cell killing that disrupts the microflora present. As a result, potentially helpful microbial cells are killed along with the pathogen, altering the biodiversity and dynamic interactions within the population. Moreover, the unwarranted exposure of antibiotics to microbes increases the likelihood of developing resistance and perpetuates the emergence of multidrug resistance. Synthetic biology offers an alternative solution where specificity can be conferred to reduce the non-specific, non-targeted activity of currently available antibiotics, and instead provides targeted therapy against specific pathogens and minimising collateral damage to the host’s inherent microbiota. With a greater understanding of the microbiome and the available genetic engineering tools for microbial cells, it is possible to devise antimicrobial strategies for novel antimicrobial therapy that are able to precisely and selectively remove infectious pathogens. Herein, we review the strategies developed by unlocking some of the natural mechanisms used by the microbes and how these may be utilised in targeted antimicrobial therapy, with the promise of reducing the current global bane of multidrug antimicrobial resistance.     

Antibiotic bioassay by flow microcalorimetry

Summary A rapid, sensitive microcalorimetric bioassay of good reproducibility has been developed for the antibiotics penicillin-G, carbenicillin, ampicillin and cefoxitin. The use of growing organisms as responding agents allows discussion of the results for systems which may involve biological fluids.Acknowledgment. We thank the Department of Health and Social Security for a grant to support this work.     

Voices from within: gut microbes and the CNS

Recent advances in research have greatly increased our understanding of the importance of the gut microbiota. Bacterial colonization of the intestine is critical to the normal development of many aspects of physiology such as the immune and endocrine systems. It is emerging that the influence of the gut microbiota also extends to modulation of host neural development. Furthermore, the overall balance in composition of the microbiota, together with the influence of pivotal species that induce specific responses, can modulate adult neural function, peripherally and centrally. Effects of commensal gut bacteria in adult animals include protection from the central effects of infection and inflammation as well as modulation of normal behavioral responses. There is now robust evidence that gut bacteria influence the enteric nervous system, an effect that may contribute to afferent signaling to the brain. The vagus nerve has also emerged as an important means of communicating signals from gut bacteria to the CNS. Further understanding of the mechanisms underlying microbiome–gut–brain communication will provide us with new insight into the symbiotic relationship between gut microbiota and their mammalian hosts and help us identify the potential for microbial-based therapeutic strategies to aid in the treatment of mood disorders.     

Antibiotic sensitivity testing by flow microcalorimetry

Summary The proposed flow microcalorimetric method for the diagnosis of bacteriuria has been extended to include antibiotic sensitivity testing. Sensitive organisms rapidly (4–8 min) show thermal responses to the added antibiotics over the normal range of concentrations (1×, 2×, MIC value).     

Antibiotic sensitivity testing by flow microcalorimetry.

The proposed flow microcalorimetric method for the diagnosis of bacteriuria has been extended to include antibiotic sensitivity testing. Sensitive organisms rapidly (4-8 min) show thermal responses to the added antibiotics over the normal range of concentrations (1 x, 2x, MIC value).     

A simple culture vessel for turbidimetric studies of anaerobic growth of microbes

Résumé La fiole de culture décrite permet le mesurage par voie turbidimétrique de la croissance microbienne en culture anaérobie et agitée. Du gaz, produit par la culture, peut s'échapper par une valve. Par l'application additionelle d'un bulbe latéral contenant de la potasse, la comparaison est possible entre des cultures parallèles, croissant soit en présence soit en absence de CO₂.

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The first author is indebted to Prof. Dr.T. O. Wikén for facilities offered to him in the Laboratory of Microbiology, Technological University, Delft.     

Antibiotic activity of deoxy-herqueinone (atrovenetin monomethyl ether)

Zusammenfassung Aus Herqueinon erhält man Desoxyherqueinon (Atrovenetin-monomethyl-äther) mit antibakteriellen Eigenschaften. Spektrum ähnlich wie Atrovenetin, obwohl die minimale Hemmungskonzentration höher liegt.     

Griseofulvin resistance in dermatophytes

Zusammenfassung Häufigkeit und Eigenschaften der griseofulvinresistenten Mutanten vonMicrosporum gypseum wurden geprüft. 2 Loci, durch welche die Resistenz gesteuert wird, wurden in verschiedenen Kopplungsgruppen identifiziert und im Vergleich mit dem Ausgangsstamm die Resistenz bei allen Mutanten hundertfach vergrössert.     

Antibiotic activity of organic compounds and their average quasi-valence number

Summary It is shown that the average quasi-valence numbers of antibiotics inhibiting protein synthesis are well defined and lie in the region of average quasi-valence numbers of amino acids, while the average quasi-valence numbers of antibiotics inhibiting DNA or RNA synthesis have higher values. Possible explanations of these findings and their implications on the design and selection of antibiotics are discussed.     

Disease resistance in farm animals

Genetic variations in disease resistance of farm animals can be observed at all levels of defence against infectious agents. In most cases susceptibility to infections has polygenic origins. In domestic animals only a few instances of a single genetic locus responsible for disease resistance are known. A well-examined example is the Mx1 gene product of certain mice strains conferring selective resistance to influenza virus infections. Attempts to improve disease resistance by gene transfer of different gene constructs into farm animals include the use of monoclonal antibody gene constructs, transgenes consisting of antisense RNA genes directed against viruses and Mx1 cDNA containing transgenes.     

Disease resistance in farm animals

Genetic variations in disease resistance of farm animals can be observed at all levels of defence against infectious agents. In most cases susceptibility to infections has polygenic origins. In domestic animals only a few instances of a single genetic locus responsible for disease resistance are known. A well-examined example is the Mx1 gene product of certain mice strains conferring selective resistance to influenza virus infections. Attempts to improve disease resistance by gene transfer of different gene constructs into farm animals include the use of monoclonal antibody gene constructs, transgenes consisting of antisense RNA genes directed against viruses and Mx1 cDNA containing transgenes.