Marcos Pires

A compound that kills both Gram-positive and Gram-negative bacteria through two independent mechanisms may provide a platform for the development of future antibiotics.

Bring on the substitutes : Pradimicins (PRMs) are unique natural products that bind d ‐mannose in the presence of Ca²⁺ ions. Recent structural elucidation of the Ca²⁺ binding of PRMs paves the way for designing novel PRM derivatives for use as lectin mimics in glycobiological research.

Abstract

Pradimicins (PRMs) constitute an exceptional class of natural products that show Ca²⁺‐dependent recognition of d ‐mannose (Man). In addition to therapeutic uses as antifungal drugs, the application of PRMs as lectin mimics for glycobiological research has been attracting considerable interest, since the emerging biological roles of Man‐containing glycans have been highlighted. However, only a few attempts have been made to use PRMs for glycobiological purposes. The limited use of PRMs is primarily due to the early assumption that the readily modifiable carboxyl group of PRMs is involved in Ca²⁺ binding, and thus, not available to prepare research tools. Recently, this assumption has been disproved by structural elucidation of the Ca²⁺ complex of PRMs, which paves the way for designing carboxyl group modified derivatives of PRMs for research use. This article outlines studies related to Ca²⁺‐mediated Man binding of PRMs and discusses their application for glycobiology.

The IgG Fc domain has the capacity to interact with diverse types of receptors, including the neonatal Fc receptor (FcRn) and Fcγ receptors (FcγRs), which confer pleiotropic biological activities. Whereas FcRn regulates IgG epithelial transport and recycling, Fc effector activities, such as antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis, are mediated...

The mechanism(s) by which cell-tethered mucins modulate infection by influenza A viruses (IAVs) remain an open question. Mucins form both a protective barrier that can block virus binding and recruit IAVs to bind cells via the sialic acids of cell-tethered mucins. To elucidate the molecular role of mucins in flu...

Ketogenic diets differ from high fat diets in that they alter the gut microbiome to affect the level of gut Th17 cells.

Cancer nanovaccines that use nanomaterials as antigens and/or adjuvant‐delivering carriers can induce tumor antigen‐specific T cell immunity and have shown potential as therapeutic modalities in in vivo animal models. Moreover, the addition of immune checkpoint blockade (ICB) immunotherapy to cancer nanovaccines can further potentiate the antitumor efficacy of the latter. However, little effort has been made to develop an optimal treatment regimen based on treatment sequence and the timing of each modality. The present study describes a small lipid nanoparticle (SLNP)‐based nanovaccine platform and a new combination treatment regimen. Tumor antigen‐displaying, CpG adjuvant‐embedded SLNPs (OVAPEP‐SLNP@CpG) were prepared from biocompatible phospholipids and a cationic cholesterol derivative. The resulting nanovaccine showed highly potent antitumor efficacy in both prophylactic and therapeutic E.G7 tumor models. However, this vaccine simultaneously induced T cell exhaustion by elevating PD‐L1 expression, leading to tumor recurrence. Thus, the nanovaccine was combined with simultaneous anti‐PD‐1 antibody treatment, but the therapeutic efficacy of this regimen was comparable to that of the nanovaccine alone. Finally, mice that showed a good therapeutic response after the first cycle of immunization with the nanovaccine underwent a second cycle of immunization together with anti‐PD‐1 therapy, resulting in effective suppression of tumor relapse. These findings suggest that the antitumor efficacy of combinations of nanovaccines with ICB therapy is dependent on treatment sequence and the timing of each modality.

Targeted protein degradation has created tremendous excitement in chemical biology and drug discovery. This Review gives a comprehensive overview of chemical biology tools as well as therapeutic approaches inducing targeted protein degradation and discusses them from a medicinal chemist's perspective.

Abstract

Targeted protein degradation (TPD), the ability to control a proteins fate by triggering its degradation in a highly selective and effective manner, has created tremendous excitement in chemical biology and drug discovery within the past decades. The TPD field is spearheaded by small molecule induced protein degradation with molecular glues and proteolysis targeting chimeras (PROTACs) paving the way to expand the druggable space and to create a new paradigm in drug discovery. However, besides the therapeutic angle of TPD a plethora of novel techniques to modulate and control protein levels have been developed. This enables chemical biologists to better understand protein function and to discover and verify new therapeutic targets. This Review gives a comprehensive overview of chemical biology techniques inducing TPD. It explains the strengths and weaknesses of these methods in the context of drug discovery and discusses their future potential from a medicinal chemist's perspective.

The rapid-acting antidepressant and antisuicidal effects of the anesthetic (R,S)-ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, is an important discovery in depression research (1). However, the precise molecular mechanisms underlying (R,S)-ketamine’s antidepressant actions remain unknown. Naltrexone, an opioid receptor antagonist, blocked the rapid antidepressant and antisuicidal effects of (R,S)-ketamine in treatment-resistant...

The steps of QAC activity : Quaternary ammonium compounds (QACs) have long been assumed to disrupt bacterial membranes through electrostatic attraction followed by intercalation and subsequent disruption, but little modeling evidence has been presented to support this; the mechanism of action of multiQACs was even less clear. In a holistic study featuring computational modeling and SAR, we examine how QACs bearing multiple cations disrupt bacterial membranes.

Abstract

The mechanism of action of quaternary ammonium compound (QAC) antiseptics has long been assumed to be straightforward membrane disruption, although the process of approaching and entering the membrane has little modeling precedent. Furthermore, questions have more recently arisen regarding bacterial resistance mechanisms, and why select classes of QACs (specifically, multicationic QACs) are less prone to resistance. In order to better understand such subtleties, a series of molecular dynamics simulations were utilized to help identify these molecular determinants, directly comparing mono‐, bis‐, and triscationic QACs in simulated membrane intercalation models. Three distinct membranes were simulated, mimicking the surfaces of Escherichia coli and Staphylococcus aureus , as well as a neutral phospholipid control. By analyzing the resulting trajectories in the form of a timeseries analysis, insight was gleaned regarding the significant steps and interactions involved in the destabilization of phospholipid bilayers within the bacterial membranes. Finally, to more specifically probe the effect of the hydrophobic section of the amphiphile that presumably penetrates the membrane, a series of alkyl‐ and ester‐based biscationic quaternary ammonium compounds were prepared, tested for antimicrobial activity against both Gram‐positive and Gram‐negative bacteria, and modeled.

The bacterial pathogen Staphylococcus aureus is capable of infecting a broad spectrum of host tissues, in part due to flexibility of metabolic programs. S. aureus, like all organisms, requires essential biosynthetic intermediates to synthesize macromolecules. We therefore sought to determine the metabolic pathways contributing to synthesis of essential precursors during...

To advance mechanistic understanding of membrane-associated peptide folding and insertion, we have studied the kinetics of three single tryptophan pHLIP (pH-Low Insertion Peptide) variants, where tryptophan residues are located near the N terminus, near the middle, and near the inserting C-terminal end of the pHLIP transmembrane helix. Single-tryptophan pHLIP variants...

Conventional drug discovery approaches are difficult to apply for the removal of the misfolded protein aggregates that are thought to cause neurodegenerative disorders (NDs). In contrast, new chemical protein degradation technologies such as PROTACs seem promising for NDs therapy, opening up the possibility of selective elimination of “undruggable” target proteins by utilizing physiological protein degradation machineries.

Abstract

Neurodegenerative disorders (NDs) are a group of diseases that cause neural cell damage, leading to motility and/or cognitive dysfunctions. One of the causative agents is misfolded protein aggregates, which are considered as undruggable in terms of conventional tools, such as inhibitors and agonists/antagonists. Indeed, there is currently no FDA‐approved drug for the causal treatment of NDs. However, emerging technologies for chemical protein degradation are opening up the possibility of selective elimination of target proteins through physiological protein degradation machineries, which do not depend on the functions of the target proteins. Here, we review recent efforts towards the treatment of NDs using chemical protein degradation technologies, and we briefly discuss the challenges and prospects.

Nature, Published online: 13 May 2020; doi:10.1038/d41586-020-01335-3

There is growing evidence that gut microbes can influence disease. Analysis of a mouse model of the neurodegenerative condition amyotrophic lateral sclerosis offers insight into how gut bacteria might contribute to this illness.

Most bacteria surround themselves with a cell wall, a strong meshwork consisting primarily of the polymerized aminosugar peptidoglycan (PG). PG is essential for structural maintenance of bacterial cells, and thus for viability. PG is also constantly synthesized and turned over; the latter process is mediated by PG cleavage enzymes, for...

Nature Microbiology, Published online: 11 May 2020; doi:10.1038/s41564-020-0721-1

A precision approach to probiotics could address the heterogeneity inherent to probiotic strains, the hosts and their microbiomes. Here, we discuss the steps required to develop precision probiotics: mechanistic studies, phenotypic and target-based discovery strategies, and person-centric trials.

Nature Microbiology, Published online: 11 May 2020; doi:10.1038/s41564-020-0719-8

In rhizosphere microbial communities, iron competition via secreted siderophores can be used as a predictor of commensal–pathogen interactions and plant protection against infection with the pathogen Ralstonia solanacearum.

The d ‐peptide ^DTBP‐3 was identified, which could effectively block TIGIT/PVR interaction. ^DTBP‐3 could inhibit tumor growth and metastasis in anti‐PD‐1 resistant tumor model and could serve as a potential candidate for cancer immunotherapy.

Abstract

The low response rate and adaptive resistance of PD‐1/PD‐L1 blockade demands the studies on novel therapeutic targets for cancer immunotherapy. We discovered that a novel immune checkpoint TIGIT expressed higher than PD‐1 in many tumors especially anti‐PD‐1 resistant tumors. Here, mirror‐image phage display bio‐panning was performed using the d ‐enantiomer of TIGIT synthesized by hydrazide‐based native chemical ligation. d ‐peptide ^DTBP‐3 was identified, which could occupy the binding interface and effectively block the interaction of TIGIT with its ligand PVR. ^DTBP‐3 showed proteolytic resistance, tumor tissue penetrating ability, and significant tumor suppressing effects in a CD8⁺ T cell dependent manner. More importantly, ^DTBP‐3 could inhibit tumor growth and metastasis in anti‐PD‐1 resistant tumor model. This is the first d ‐peptide targeting TIGIT, which could serve as a potential candidate for cancer immunotherapy.

by Etthel M. Windels, Bram Van den Bergh, Jan Michiels

Bacteria are well known for their extremely high adaptability in stressful environments. The clinical relevance of this property is clearly illustrated by the ever-decreasing efficacy of antibiotic therapies. Frequent exposures to antibiotics favor bacterial strains that have acquired mechanisms to overcome drug inhibition and lethality. Many strains, including life-threatening pathogens, exhibit increased antibiotic resistance or tolerance, which considerably complicates clinical practice. Alarmingly, recent studies show that in addition to resistance, tolerance levels of bacterial populations are extremely flexible in an evolutionary context. Here, we summarize laboratory studies providing insight in the evolution of resistance and tolerance and shed light on how the treatment conditions could affect the direction of bacterial evolution under antibiotic stress.

Nature, Published online: 06 May 2020; doi:10.1038/s41586-020-2269-x

A cross-sectional analysis of participants in the MetaCardis Body Mass Index Spectrum cohort finds that the higher prevalence of gut microbiota dysbiosis in individuals with obesity is not observed in those who take statin drugs.

ABSTRACT

Rod-shaped bacteria frequently localize proteins to one or both cell poles in order to regulate processes such as chromosome replication or polar organelle development. However, the roles of polar factors in responses to extracellular stimuli have been generally unexplored. We employed chemical-genetic screening to probe the interaction between one such factor from Caulobacter crescentus, TipN, and extracellular stress and found that TipN is required for normal resistance of cell envelope-directed antibiotics, including vancomycin which does not normally inhibit growth of Gram-negative bacteria. Forward genetic screening for suppressors of vancomycin sensitivity in the absence of TipN revealed the TonB-dependent receptor ChvT as the mediator of vancomycin sensitivity. Loss of ChvT improved resistance to vancomycin and cefixime in the otherwise sensitive tipN strain. The activity of the two-component system regulating ChvT (ChvIG) was increased in tipN cells relative to the wild type under some, but not all, cell wall stress conditions that this strain was sensitized to, in particular cefixime and detergent exposure. Together, these results indicate that TipN contributes to cell envelope stress resistance in addition to its roles in intracellular development, and its loss influences signaling through the ChvIG two-component system which has been co-opted as a sensor of cell wall stress in Caulobacter.

IMPORTANCE Maintenance of an intact cell envelope is essential for free-living bacteria to protect themselves against their environment. In the case of rod-shaped bacteria, the poles of the cell are potential weak points in the cell envelope due to the high curvature of the layers and the need to break and reform the cell envelope at the division plane as the cells divide. We have found that TipN, a factor required for correct division and cell pole development in Caulobacter crescentus, is also needed for maintaining normal levels of resistance to cell wall-targeting antibiotics such as vancomycin and cefixime, which interfere with peptidoglycan synthesis. Since TipN is normally located at the poles of the cell and at the division plane just before cells complete division, our results suggest that it is involved in stabilization of these weak points of the cell envelope as well as its other roles inside the cell.

Antimicrobial peptides (AMPs) are essential components of immune defenses of multicellular organisms and are currently in development as anti-infective drugs. AMPs have been classically assumed to have broad-spectrum activity and simple kinetics, but recent evidence suggests an unexpected degree of specificity and a high capacity for synergies. Deeper evaluation of the molecular evolution and population genetics of AMP genes reveals more evidence for adaptive maintenance of polymorphism in AMP genes than has previously been appreciated, as well as adaptive loss of AMP activity. AMPs exhibit pharmacodynamic properties that reduce the evolution of resistance in target microbes, and AMPs may synergize with one another and with conventional antibiotics. Both of these properties make AMPs attractive for translational applications. However, if AMPs are to be used clinically, it is crucial to understand their natural biology in order to lessen the risk of collateral harm and avoid the crisis of resistance now facing conventional antibiotics.