Antibiotics: past, present and future

The first antibiotic, salvarsan, was deployed in 1910. In just over 100 years antibiotics have drastically changed modern medicine and extended the average human lifespan by 23 years. The discovery of penicillin in 1928 started the golden age of natural product antibiotic discovery that peaked in the mid-1950s. Since then, a gradual decline in antibiotic discovery and development and the evolution of drug resistance in many human pathogens has led to the current antimicrobial resistance crisis. Here we give an overview of the history of antibiotic discovery, the major classes of antibiotics and where they come from. We argue that the future of antibiotic discovery looks bright as new technologies such as genome mining and editing are deployed to discover new natural products with diverse bioactivities. We also report on the current state of antibiotic development, with 45 drugs currently going through the clinical trials pipeline, including several new classes with novel modes of action that are in phase 3 clinical trials. Overall, there are promising signs for antibiotic discovery, but changes in financial models are required to translate scientific advances into clinically approved antibiotics

In Situ Activation and Heterologous Production of a Cryptic Lantibiotic from an African Plant Ant-Derived Saccharopolyspora Species.

Most clinical antibiotics are derived from actinomycete natural products discovered at least 60 years ago. However, the repeated rediscovery of known compounds led the pharmaceutical industry to largely discard microbial natural products (NPs) as a source of new chemical diversity. Recent advances in genome sequencing have revealed that these organisms have the potential to make many more NPs than previously thought. Approaches to unlock NP biosynthesis by genetic manipulation of strains, by the application of chemical genetics, or by microbial cocultivation have resulted in the identification of new antibacterial compounds. Concomitantly, intensive exploration of coevolved ecological niches, such as insect-microbe defensive symbioses, has revealed these to be a rich source of chemical novelty. Here, we report the new lanthipeptide antibiotic kyamicin, which was generated through the activation of a cryptic biosynthetic gene cluster identified by genome mining Saccharopolyspora species found in the obligate domatium-dwelling ant Tetraponera penzigi of the ant plant Vachellia drepanolobium Transcriptional activation of this silent gene cluster was achieved by ectopic expression of a pathway-specific activator under the control of a constitutive promoter. Subsequently, a heterologous production platform was developed which enabled the purification of kyamicin for structural characterization and bioactivity determination. This strategy was also successful for the production of lantibiotics from other genera, paving the way for a synthetic heterologous expression platform for the discovery of lanthipeptides that are not detected under laboratory conditions or that are new to nature.IMPORTANCE The discovery of novel antibiotics to tackle the growing threat of antimicrobial resistance is impeded by difficulties in accessing the full biosynthetic potential of microorganisms. The development of new tools to unlock the biosynthesis of cryptic bacterial natural products will greatly increase the repertoire of natural product scaffolds. Here, we report a strategy for the ectopic expression of pathway-specific positive regulators that can be rapidly applied to activate the biosynthesis of cryptic lanthipeptide biosynthetic gene clusters. This allowed the discovery of a new lanthipeptide antibiotic directly from the native host and via heterologous expression

A search for the first massive galaxy clusters

We have obtained deep, multi-band imaging observations around three of the most distant known quasars at redshifts z>6. Standard accretion theory predicts that the supermassive black holes present in these quasars were formed at a very early epoch. If a correlation between black hole mass and dark matter halo mass is present at these early times, then these rare supermassive black holes will be located inside the most massive dark matter halos. These are therefore ideal locations to search for the first clusters of galaxies. We use the Lyman-break technique to identify star-forming galaxies at high redshifts. Our observations show no overdensity of star-forming galaxies in the fields of these quasars. The lack of (dust-free) luminous starburst companions indicates that the quasars may be the only massive galaxies in their vicinity undergoing a period of intense activity.Comment: 6 pages, 2 figures, contributed paper to Proceedings of the Conference "Growing Black Holes" held in Garching, Germany, June 21-25, 2004, edited by A. Merloni, S. Nayakshin and R. Sunyaev, Springer-Verlag series of "ESO Astrophysics Symposia

Nuclear obscuration and scattering in Seyfert 2 galaxies

We study the relation between gaseous absorbing column density (N$_{\rm H}$), infrared colors and detectability of the broad lines in a large sample of Seyfert 2 galaxies(Sy2s). We confirm that Sy2s without polarized broad lines tend to have cooler 60$\mu$m/25$\mu$m colors; this correlation was previously ascribed to the effect of obscuration towards the nuclear region. We find some evidence that Sy2s without polarized broad lines have larger absorbing column density (N$_{\rm H}$) and that a fraction of them are characterized by dust lanes crossing their nuclei. However, we find that the IR colors do not correlate with N$_{\rm H}$, in disagreement with the obscuration scenario. Also, Sy2s without polarized broad lines follow the same radio-FIR relation as normal and starburst galaxies, at variance with Sy2s with polarized broad lines. These results indicate that the lack of broad lines in the polarized spectrum of Sy2s is mostly due to the contribution/dilution from the host galaxy or from a circumnuclear starburst, though at a lower extent the obscuration toward the nuclear region also plays a role.Comment: 6 pages, 4 figures, to appear in A&A

XMM-Newton observation of PG 0844 + 349

In a ~ 20 ksec XMM-Newton observation the X-ray transient radio-quiet quasar PG 0844+349 was found in a historically high state compared to previous X-ray observations. The quasar showed a featureless spectrum with a strong soft excess over the extrapolation of a hard power law. Comptonization models or a broken power law with Gamma_{soft} ~ 2.75, Gamma_{hard} ~ 2.25 and a break energy of E_{break} ~ 1.35 keV represent acceptable descriptions of the spectral continuum. In the Comptonization models the temperature of the Comptonizing gas is considerably lower than generally found in (broad line) Seyfert galaxies whereas the optical depth is much higher. As a similar behavior has been seen in NLSy1 galaxies, it might be an indicator of the different physical conditions in these two classes of AGN. During the XMM-Newton observation the flux of PG 0844+349 varied achromatically in a smooth, nearly linear fashion, by ~ 25 % on time scales of a few thousand seconds, which puts some constraints on current models of Comptonizing accretion disk coronae.Comment: 7 pages, 4 figures. A&A accepte

The dust-enshrouded microquasar candidate AX J1639.0-4642 = IGR J16393-4643

We present a multiwavelength study of the field containing the unidentified X-ray source AX J1639.0-4642, discovered with the ASCA observatory and recently detected with the IBIS telescope, onboard the INTEGRAL satellite, dubbed IGR J16393-4643. The huge hydrogen column density towards the source, the hard spectral index in the 0.7-10 keV band and its flux variability suggest that the source is a High Mass X-ray Binary (HMXB) enshrouded by dust. Our search reveals the presence of a non-thermal radio counterpart within the X-ray error box. After a study of the broadband emission from X-rays to the radio domain, we propose that AX J1639.0-4642 is a dust-enshrouded Microquasar (MQ) candidate. In addition, the X-ray source is well within the 95% location contour of the unidentified gamma-ray source 3EG J1639-4702. The main properties of AX J1639.0-4642/3EG J1639-4702 are consistent with those of two other MQs previously proposed to display high-energy gamma-ray emission.Comment: 7 pages, 5 figures. Accepted for publication in A&A. Title and discussion on the possible NIR counterpart have been modifie

The environments of z~1 Active Galactic Nuclei at 3.6um

We present an analysis of a large sample of AGN environments at z~1 using stacked Spitzer data at 3.6um. The sample contains type-1 and type-2 AGN in the form of quasars and radio galaxies, and spans a large range in both optical and radio luminosity. We find, on average, that 2 to 3 massive galaxies containing a substantial evolved stellar population lie within a 200-300 kpc radius of the AGN, constituting a >8-sigma excess relative to the field. Secondly, we find evidence for the environmental source density to increase with the radio luminosity of AGN, but not with black-hole mass. This is shown first by dividing the AGN into their classical AGN types, where we see more significant over-densities in the fields of the radio-loud AGN. If instead we dispense with the classical AGN definitions, we find that the source over-density as a function of radio luminosity for all our AGN exhibits a positive correlation. One interpretation of this result is that the Mpc-scale environment is in some way influencing the radio emission that we observe from AGN. This could be explained by the confinement of radio jets in dense environments leading to enhanced radio emission or, alternatively, may be linked to more rapid black-hole spin brought on by galaxy mergers.Comment: 13 pages, 12 figures, accepted by MNRA

Chandra unveils a binary Active Galactic Nucleus in Mrk463

We analyse Chandra, XMM-Newton and HST data of the double-nucleus Ultraluminous Infrared Galaxy (ULIRG), Mrk463. The Chandra detection of two luminous ($\mathrm{L}_\mathrm{2-10 keV}=1.5\times10^{43}$ and $3.8\times10^{42}$ erg cm$^{-2}$ s$^{-1}$), unresolved nuclei in Mrk~463 indicates that this galaxy hosts a binary AGN, with a projected separation of $\simeq3.8$ kpc ($3.83\pm0.01$ arcsec). While the East nucleus was already known to be a Seyfert 2 (and this is further confirmed by our Chandra detection of a neutral iron line), this is the first unambiguous evidence in favour of the AGN nature of the West nucleus. Mrk463 is therefore the clearest case so far for a binary AGN, after NGC6240.Comment: 7 pages, 7 figures, accepted for publication in MNRA

Streptomyces endophytes promote host health and enhance growth across plant species

Streptomyces bacteria are ubiquitous in soils and are well-known for producing secondary metabolites, including antimicrobials. Increasingly, they are being isolated from plant roots and several studies have shown they are specifically recruited to the rhizosphere and the endosphere of the model plant Arabidopsis thaliana Here we test the hypothesis that Streptomyces bacteria have a beneficial effect on A. thaliana growth and could potentially be used as plant probiotics. To do this, we selectively isolated streptomycetes from surface washed A. thaliana roots and generated high quality genome sequences for five strains which we named L2, M2, M3, N1 and N2. Re-infection of A. thaliana plants with L2, M2 and M3 significantly increased plant biomass individually and in combination whereas N1 and N2 had a negative effect on plant growth, likely due to their production of polyene natural products which can bind to phytosterols and reduce plant growth. N2 exhibits broad spectrum antimicrobial activity and makes filipin-like polyenes, including 14-hydroxyisochainin which inhibits the Take-all fungus, Gaeumannomyces graminis var. tritici N2 antifungal activity as a whole was upregulated ∼2-fold in response to indole-3-acetic acid (IAA) suggesting a possible role during competition in the rhizosphere. Furthermore, coating wheat seeds with N2 spores protected wheat seedlings against Take-all disease. We conclude that at least some soil dwelling streptomycetes confer growth promoting benefits on A. thaliana while others might be exploited to protect crops against disease.Importance. We must reduce reliance on agrochemicals and there is increasing interest in using bacterial strains to promote plant growth and protect against disease. Our study follows up reports that Arabidopsis thaliana specifically recruits Streptomyces bacteria to its roots. We test the hypothesis that they offer benefits to their A. thaliana hosts and that strains isolated from these plants might be used as probiotics. We isolated Streptomyces strains from A. thaliana roots and genome sequenced five phylogenetically distinct strains. Genome mining and bioassays indicated that all five have plant growth promoting properties, including production of IAA, siderophores and ACC deaminase. Three strains significantly increased A. thaliana growth in vitro and in combination in soil. Another produces potent filipin-like antifungals and protected germinating wheat seeds against the fungal pathogen Gaeumannomyces graminis var. tritici (wheat Take-all fungus). We conclude that introducing Streptomyces strains into the root microbiome provides significant benefits to plants