Marcos Pires

Proceedings of the National Academy of Sciences, Volume 123, Issue 22, June 2026.
SignificanceDuring host colonization or infection, bacteria encounter spatially constrained environments, such as deep-seated infected tissues or abscesses that impose mechanical stress. As they grow under confinement, they generate internal forces whose ...

Nature, Published online: 06 May 2026; doi:10.1038/s41586-026-10459-x

A large-scale proteomics analysis of the dark proteome by the TransCODE Consortium reveals many translated non-canonical open reading frames to encode microproteins and peptideins.

Ternary solvents of water, a water-miscible polar organic solvent, and oil can form nanophases that modulate click reaction kinetics. Rate enhancement occurs for a select range of ternary compositions only when hydrophobic reactants are used. Reagent co-localization inside oil-in-water nanophases is proposed as the mechanism for rate enhancement.

Nature Biotechnology, Published online: 16 April 2026; doi:10.1038/s41587-026-03078-4

Diversity-generating retroelements are engineered for directed evolution in E.coli.

Nature Biotechnology, Published online: 10 March 2026; doi:10.1038/s41587-026-03018-2

Surveying recent progress in neoantigen cancer vaccine development, this Review highlights areas where further technological advances and optimized trial design could enhance clinical impact.

Nature, Published online: 25 February 2026; doi:10.1038/s41586-026-10163-w

A common mechanism of inhibition of the essential lipid II flippase MurJ by three distinct phage-encoded single-gene lysis proteins provides insights into potential new targets for antimicrobial development.

Proceedings of the National Academy of Sciences, Volume 123, Issue 4, January 2026.
SignificancePolyglutamine (polyQ) aggregates are a hallmark of Huntington’s Disease (HD), yet their molecular mechanisms and pathological roles remain elusive. Here, we establish a noninvasive platform to quantitatively study polyQ aggregates in live ...

Small molecule–regulated protein oligomerization provides a powerful mechanism for manipulating biological processes by controlling protein proximity with high temporal precision. However, such systems only rarely exist in nature and remain a substantial ...

Nature Microbiology, Published online: 01 December 2025; doi:10.1038/s41564-025-02211-4

We uncover hundreds of inhibitory interactions between industrial and agricultural chemicals and gut bacteria. Systematic genetic analyses reveal bacterial survival mechanisms against pollutants and their commonality with antibiotic resistance. Our data enable machine learning-based predictive toxicology and make a case for considering antibacterial activity in chemical safety assessment.

Nature Microbiology, Published online: 26 November 2025; doi:10.1038/s41564-025-02182-6

Screening of 1,076 compounds reveals 168 chemical pollutants with inhibitory effects on gut bacteria and genetic screens indicate commonality between pollutant and antibiotic resistance.

Proceedings of the National Academy of Sciences, Volume 122, Issue 47, November 2025.
SignificanceT cells patrol short peptides displayed by MHC molecules to protect the body from infection and cancer. While there are currently computational approaches to predict which peptides will bind to major histocompatibility complexes (MHCs), they ...

Nature Microbiology, Published online: 24 November 2025; doi:10.1038/s41564-025-02175-5

The permeability of bacterial porins is dynamically regulated by periplasmic proton and potassium concentrations, altering antibiotic resistance.

Nature Communications, Published online: 10 November 2025; doi:10.1038/s41467-025-65481-w

Conventional PROTACs have limited capacity for misfolded proteins. Here, authors develop a BioPROTAC containing an scFv specifically targeting misfolded SOD1, fused to an E3 ligase, and demonstrate a strategy for reducing misfolded SOD1 accumulation.

Nature, Published online: 18 June 2025; doi:10.1038/s41586-025-09177-7

The validation of inhibitors targeting PurF, a novel drug target for tuberculosis drug discovery, is described.

Nature Chemical Biology, Published online: 19 June 2025; doi:10.1038/s41589-025-01944-x

This Perspective discusses click biology as an analogy to click chemistry and examines reactions carried out using building blocks present in every living cell, enabling rapid selective covalent bond formation under biologically friendly conditions. Desirable criteria for robust cellular performance are defined, along with new opportunities arising from click biology for fundamental research and synthetic biology.

The electrostatic profile of sortase A pentamutant (SrtA-5M) is leveraged to improve SrtA-5M-mediated transpeptidations by incorporating short, charged peptidic modules into the substrates. The reaction is highly efficient, straightforward to implement, compatible with recombinant protein expression, and enables remarkably clean protein labeling and protein-protein coupling.

Abstract

Sortase-mediated transpeptidation is a powerful biochemical reaction to perform protein engineering. In this work, we leverage the unique electrostatic profile of sortase A pentamutant (SrtA-5M) to improve SrtA-5M-mediated transpeptidations by incorporating short, charged peptidic modules into the substrates. Importantly, the reaction proceeds with a minimal excess of nucleophile and is fast and highly efficient in the low micromolar substrate concentration range. Electrostatic assistance eliminates the need for additives or complex substrate engineering strategies, thereby giving it a broad scope. Our findings also provide fundamental insights into the influence of substrate charge on SrtA-5M activity, paving the way for further optimization of sortase A-catalyzed transpeptidation reactions.

Nature, Published online: 26 March 2025; doi:10.1038/s41586-025-08723-7

A new lasso peptide antibiotic exhibits broad-spectrum activity against Gram-negative and Gram-positive bacteria by interfering with bacterial protein synthesis, is unaffected by common resistance mechanisms and shows no toxicity towards human cells.

Gromomycins represent a novel class of pentacyclic triterpene antibiotics with a unique biosynthetic pathway independent of the squalene route. These compounds exhibit potent activity against drug-resistant Gram-positive pathogens, including MRSA, and their unprecedented cyclization mechanism provides new insight into bacterial triterpene biosynthesis.

Abstract

The current situation with drug-resistant microbial pathogens is critical, dictating an acute need for novel efficient antibiotics. Herein, we report a new class of antibiotics named gromomycins with significant activity, especially against drug-resistant Gram-positive pathogens, including methicillin- and daptomycin-resistant Staphylococcus aureus. Gromomycins are pentacyclic triterpenes with a cyclic guanidino group forming the fifth six-membered ring. We have used transposon mutagenesis to identify the gromomycin biosynthetic gene cluster, since it could not be assigned by any available bioinformatics tools, highlighting its unique biosynthetic route. Using gene cluster engineering, feeding experiments, and LC-MS and NMR analyses we have proposed the biosynthetic pathway for gromomycins, which are the first bacterial triterpenes synthesized independently of the squalene pathway. They also exhibit a so far unprecedented cyclization route that utilizes a hexaprenylguanidine linear precursor. Leveraging our understanding of their biosynthesis, we have identified additional gromomycin producers, resulting in the isolation of novel bioactive derivatives.

Combining rotationally symmetric [Me-Pr-dabco]²⁺ dications with the noncentrosymmetric [MnX₄]²⁻ coordination tetrahedra, a pair of Mn²⁺-based halide enantiomeric hybrids (P-1 and M-1) were self-assembled from achiral molecular architectures, which exhibit exceptionally high CPL performance with a record-high figure of merit (FM) of 4.2 × 10⁻² and remarkable luminous brightness (74 5912 cd m⁻²) among reported Mn²⁺-based CPL materials.

Abstract

Circularly polarized luminescence (CPL)-active materials have attracted considerable attention due to their potential applications in various advanced technological fields. CPL activity typically requires compounds that crystallize in noncentrosymmetric chiral space groups. Achieving noncentrosymmetric crystal structures using achiral molecular architectures is highly appealing but remains a significant challenge. Herein, we present a strategy for designing and synthesizing high-performance CPL materials via crystallization-driven self-assembly using achiral architectures. We successfully obtained Mn²⁺-based halide enantiomeric hybrids (P-1 and M-1), self-assembled from [MnBr₄]²⁻ anions and rotational symmetric [Pr-dabco]²⁺ cations (Pr-dabco²⁺ = 1-propyl-1,4-diazabicyclo-[2.2.2]octan-1-ium), crystallizing in the chiral space group P2₁2₁2₁. The single crystals of 1 exhibit exceptionally high CPL performance, with a luminescence dissymmetry factor |g _lum| and photoluminescence quantum yield (PLQY) up to 4.8 × 10⁻² and 86.8%, respectively, thus a record-high figure of merit (FM) of 4.2 × 10⁻² among reported Mn²⁺-based CPL materials. Furthermore, P/M-1 based UV-LED devices demonstrated outstanding light-emitting performance, including high color-purity, excellent stability, remarkable luminous brightness (74 591.94 cd m⁻²), and a high electroluminescence dissymmetry factor (g _lum) value of 3.2 × 10⁻². This study offers a robust strategy for the design and development of high-performance CPL materials utilizing achiral molecular architectures.

Jin et al. present an antibiotic target discovery framework that integrates phenotypic screening of cysteine-reactive fragments with competitive activity-based protein profiling to functionally characterize the targets of identified hits. The hit fragment, 10-F05, covalently modifies Cys112 of FabH and Cys273 of MiaA to inhibit bacterial growth, stress resistance, and virulence.