There is growing global recognition that the continued emergence of multidrug-resistant bacteria poses a serious threat to human health. Action plans released by the World Health Organization and governments of the UK and USA in particular recognize that discovering new antibiotics, particularly those with new modes of action, is one essential element required to avert future catastrophic pandemics. This review lists the 30 antibiotics and two β-lactamase/β-lactam combinations first launched since 2000, and analyzes in depth seven new antibiotics and two new β-lactam/β-lactamase inhibitor combinations launched since 2013. The development status, mode of action, spectra of activity and genesis (natural product, natural product-derived, synthetic or protein/mammalian peptide) of the 37 compounds and six β-lactamase/β-lactam combinations being evaluated in clinical trials between 2013 and 2015 are discussed. Compounds discontinued from clinical development since 2013 and new antibacterial pharmacophores are also reviewed.

Antibiotics in the clinical pipeline at the end of 2015

Streptomyces as a plant's best friend?

Antibiotic resistance constitutes one of the most pressing public health concerns. Antimicrobial peptides (AMPs) of multicellular organisms are considered part of a solution to this problem, and AMPs produced by bacteria such as colistin are last-resort drugs. Importantly, AMPs differ from many antibiotics in their pharmacodynamic characteristics. Here we implement these differences within a theoretical framework to predict the evolution of resistance against AMPs and compare it to antibiotic resistance. Our analysis of resistance evolution finds that pharmacodynamic differences all combine to produce a much lower probability that resistance will evolve against AMPs. The finding can be generalized to all drugs with pharmacodynamics similar to AMPs. Pharmacodynamic concepts are familiar to most practitioners of medical microbiology, and data can be easily obtained for any drug or drug combination. Our theoretical and conceptual framework is, therefore, widely applicable and can help avoid resistance evolution if implemented in antibiotic stewardship schemes or the rational choice of new drug candidates.

https://royalsocietypublishing.org/doi/pdf/10.1098/rspb.2017.2687

Predicting drug resistance evolution: insights from antimicrobial peptides and antibiotics.

Superimposed surface plasma resonance effect enhanced the near-infrared photocatalytic activity of Au@Bi2WO6 coating for rapid bacterial killing.

Cooperation has been studied extensively across the tree of life, from eusociality in insects to social behavior in humans, but it is only recently that a social dimension has been recognized and extensively explored for microbes. Research into microbial cooperation has accelerated dramatically and microbes have become a favorite system because of their fast evolution, their convenience as lab study systems and the opportunity for molecular investigations. However, the study of microbes also poses significant challenges, such as a lack of knowledge and an inaccessibility of the ecological context (used here to include both the abiotic and the biotic environment) under which the trait deemed cooperative has evolved and is maintained. I review the experimental and theoretical evidence in support of the limitations of the study of social behavior in microbes in the absence of an ecological context. I discuss both the need and the opportunities for experimental investigations that can inform a theoretical framework able to reframe the general questions of social behavior in a clear ecological context and to account for eco-evolutionary feedback.

/pdf/the-ecology-and-evolution-of-social-behavior-in-microbes-32zvz32rbo.pdf

The ecology and evolution of social behavior in microbes.

Nature 517, 455–459 (2015); doi:10.1038/nature14098 In Fig. 3d of this Article, the ‘2:1’ and ‘1:1’ labels at the bottom of the panel were inadvertently switched during the production process; this figure has now been corrected in the online versions of the paper.

/pdf/erratum-a-new-antibiotic-kills-pathogens-without-detectable-4bt6o0g0yf.pdf

Erratum: A new antibiotic kills pathogens without detectable resistance

High-resolution fMRI in the sub-millimeter regime allows researchers to resolve brain activity across cortical layers and columns non-invasively. While these high-resolution data make it possible to address novel questions of directional information flow within and across brain circuits, the corresponding data analyses are challenged by MRI artifacts, including image blurring, image distortions, low SNR, and restricted coverage. These challenges often result in insufficient spatial accuracy of conventional analysis pipelines. Here we introduce a new software suite that is specifically designed for layer-specific functional MRI: LayNii. This toolbox is a collection of command-line executable programs written in C/C++ and is distributed open-source and as pre- compiled binaries for Linux, Windows, and macOS. LayNii is designed for layer-fMRI data that suffer from SNR and coverage constraints and thus cannot be straightforwardly analyzed in alternative software packages. Some of the most popular programs of LayNii contain layerification and columnarization in the native voxel space of functional data as well as many other layer-fMRI specific analysis tasks: layer- specific smoothing, model-based deveining of GE-BOLD data, quality assessment of artifact dominated sub-millimeter fMRI, as well as analyses of VASO data.

https://www.biorxiv.org/content/biorxiv/early/2020/11/24/2020.06.12.148080.full.pdf

LayNii: A software suite for layer-fMRI. revision 1

Bacterial galactosemia or "galactose death," triggered by incomplete galactose metabolism, was first discovered in Escherichia coli and Salmonella six decades ago, and later in many other microorganisms, yet the mechanism for the toxicity and subsequent cell death remains unclear. In Bacillus subtilis, galactosemia is manifested by a buildup of uridine-diphosphate-galactose (UDP-Gal) and a strong toxicity phenotype characterized by cell shape abnormality and rapid cell lysis. Here we present evidence that in B. subtilis, the toxicity is due to inhibition of cell wall biosynthesis through interference of the essential glycosyltransferase MurG that carries out lipid II synthesis from lipid I and uridine-diphosphate-N-acetyl-glucosamine (UDP-GlcNAc). Single-molecule imaging reveals real-time inhibition of cell wall biosynthesis and MurG activities in cells exhibiting toxicity. We further show that in vitro, MurG is able to utilize UDP-Gal as a substrate generating a "toxic" lipid II, causing a potential poisoning effect on peptidoglycan crosslinking. Evidence also suggests a similar mechanism in Vibrio cholerae and Staphylococcus aureus. Lastly, a strong synergistic lethality was seen in S. aureus wild-type cells treated with both galactose and sub-lethal doses of cell-wall antibiotics. Our study provides mechanistic explanation of the toxicity associated with bacterial galactosemia and its potential application in antibacterial solutions. SignificanceGalactosemia is a potentially fatal genetic disorder due to incomplete galactose metabolism, found in both eukaryotic and prokaryotic organisms. The molecular mechanisms of galactosemia-associated toxicity remain unclear in all cases. Here we present evidence that in the bacterium Bacillus subtilis, the toxicity is due to interference of an essential glycosyltransferase, MurG, which concerts lipid I to lipid II during peptidoglycan biosynthesis, by a nucleotide sugar derived from galactose metabolism. This interference leads to a halt of cell wall biosynthesis and structural defects causing rapid cell lysis. Our evidence also suggests a similar mechanism in other bacteria such as Staphylococcus aureus and Vibrio cholerae. Our study may help solve the long-time puzzle of bacterial galactosemia first uncovered six decades ago.

https://www.biorxiv.org/content/biorxiv/early/2021/01/22/2021.01.22.426804.full.pdf

Anna Mueller

Papers

Erratum: A new antibiotic kills pathogens without detectable resistance

LayNii: A software suite for layer-fMRI. revision 1

Bacterial galactosemia is caused by cytoplasmic interference of an essential cell wall biosynthesis glycosyltransferase