There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

50 Years of Image Analysis

The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large. The evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens has made diseases that were once easily treatable deadly again. Unfortunately, accompanying the rise in global resistance is a failure in antibacterial drug discovery. Lessons from the history of antibiotic discovery and fresh understanding of antibiotic action and the cell biology of microorganisms have the potential to deliver twenty-first century medicines that are able to control infection in the resistance era.

Antibacterial drug discovery in the resistance era

Dangerous, antibiotic resistant bacteria have been observed with increasing frequency over the past several decades. In this review the factors that have been linked to this phenomenon are addressed. Profiles of bacterial species that are deemed to be particularly concerning at the present time are illustrated. Factors including economic impact, intrinsic and acquired drug resistance, morbidity and mortality rates, and means of infection are taken into account. Synchronously with the waxing of bacterial resistance there has been waning antibiotic development. The approaches that scientists are employing in the pursuit of new antibacterial agents are briefly described. The standings of established antibiotic classes as well as potentially emerging classes are assessed with an emphasis on molecules that have been clinically approved or are in advanced stages of development. Historical perspectives, mechanisms of action and resistance, spectrum of activity, and preeminent members of each class are discussed.

Antibiotics and Bacterial Resistance in the 21st Century

Bacteria use quorum sensing to orchestrate gene expression programmes that underlie collective behaviours. Quorum sensing relies on the production, release, detection and group-level response to extracellular signalling molecules, which are called autoinducers. Recent work has discovered new autoinducers in Gram-negative bacteria, shown how these molecules are recognized by cognate receptors, revealed new regulatory components that are embedded in canonical signalling circuits and identified novel regulatory network designs. In this Review we examine how, together, these features of quorum sensing signal-response systems combine to control collective behaviours in Gram-negative bacteria and we discuss the implications for host-microbial associations and antibacterial therapy.

/pdf/quorum-sensing-signal-response-systems-in-gram-negative-ncsir2ms1j.pdf

Quorum sensing signal–response systems in Gram-negative bacteria

Biologically active molecules can be identified through the screening of small-molecule libraries. Deficiencies in current compound collections are evidenced by the continuing decline in drug-discovery successes. Typically, such collections are comprised of large numbers of structurally similar compounds. A general consensus has emerged that library size is not everything; library diversity, in terms of molecular structure and thus function, is crucial. Diversity-oriented synthesis (DOS) aims to generate such structural diversity in an efficient manner. Recent years have witnessed significant achievements in the field, which help to validate the usefulness of DOS as a tool for the discovery of novel, biologically interesting small molecules.

/pdf/diversity-oriented-synthesis-as-a-tool-for-the-discovery-of-clriq0tput.pdf

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

Numerous species of bacteria employ a mechanism of intercellular communication known as quorum sensing. This signaling process allows the cells comprising a bacterial colony to coordinate their gene expression in a cell-density dependent manner.1-3 Quorum sensing is mediated by small diffusible molecules termed autoinducers that are synthesized intracellularly (throughout the growth of the bacteria) and released into the surrounding milieu. As the number of cells in a bacterial colony increases, so does the extracellular concentration of the autoinducer. Once a threshold concentration is reached (at which point the population is considered to be “quorate”), productive binding of the autoinducer to cognate receptors within the bacterial cells occurs, triggering a signal transduction cascade that results in population-wide changes in gene expression.4-6 Thus, quorum sensing enables the cells within a bacterial colony to act cooperatively, facilitating population-dependent adaptive behavior.6 Quorum sensing has been shown to play a critical role in both pathogenic and symbiotic bacteria-host interactions.5 In symbionts, significant quorum sensing phenotypes include bioluminescence and root nodulation.7-11 Several clinically relevant pathogens use quorum sensing systems to regulate processes associated with virulence; this enhances the survival prospects of the bacteria because a coordinated attack on the host is only made when the bacterial population reaches a high population density, increasing the likelihood that the hosts defenses will be successfully overwhelmed.12,13 For example, in Pseudomonas aeruginosa, quorum sensing is involved in the formation of biofilms and their tolerance to antimicrobial agents14-17 and the innate host immune * To whom correspondence should be addressed. Tel.: +44 (0)1223 336498. Fax: +44 (0)1223 336362. E-mail: spring@ch.cam.ac.uk. † Department of Chemistry. ‡ Department of Biochemistry. Chem. Rev. 2011, 111, 28–67 28

http://www-spring.ch.cam.ac.uk/publications/pdf/2011_CR_28.pdf

Quorum sensing in Gram-negative bacteria: small-molecule modulation of AHL and AI-2 quorum sensing pathways.

The palladium catalysed cross-coupling of organosilicon reagents with organo halides and pseudo-halides has developed over the past 30 years into an efficient and attractive carbon–carbon bond forming strategy. Extensive research within this field to expand and diversify on the scope of the organosilicon coupling reaction will continue to promote its use in the synthesis of biologically and pharmaceutically important organic molecules. The recent advances made within this area are explored in this critical review (199 references).

Palladium-catalysed cross-coupling of organosilicon reagents

http://www-spring.ch.cam.ac.uk/publications/pdf/2012_TIM_449.pdf

Warren R. J. D. Galloway

Papers

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

Quorum sensing in Gram-negative bacteria: small-molecule modulation of AHL and AI-2 quorum sensing pathways.

Palladium-catalysed cross-coupling of organosilicon reagents

Applications of small molecule activators and inhibitors of quorum sensing in Gram-negative bacteria

The discovery of antibacterial agents using diversity-oriented synthesis