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The gram-negative cell envelope is a barrier that protects the cell from environmental stress. Therefore, the synthesis of each layer of this envelope needs to be closely coordinated throughout growth and division. Here, we investigated SanA, a protein in Escherichia coli K-12 that affects envelope permeability under cellular stress, including nutrient limitation and high temperature. We found that SanA plays a key role in maintaining the permeability barrier when precursor levels for peptidoglycan (PG) synthesis are elevated, linking envelope integrity to balanced septal PG production during cell division. Our results suggest that SanA modulates substrate availability to preserve envelope function, and that in its absence, imbalanced substrate flux to septal PG synthesis disrupts septum formation and compromises barrier integrity.

M. tuberculosis remains an important public health threat, with more than one million deaths every year. The pathogen’s ability to survive in the human host for decades highlights the importance of understanding how this bacterium regulates and coordinates its metabolism, cell envelope elongation, and growth. The IMD is a membrane structure that associates with the subpolar growth zone of actively growing mycobacterial cell, but its existence is only known in a non-pathogenic model, M. smegmatis . Here, we demonstrated the presence of the IMD in M. tuberculosis , making the IMD an evolutionarily conserved plasma membrane compartment in mycobacteria. Furthermore, our study revealed that the IMD may function as the factory for synthesizing phenolic glycolipids, virulence factors produced by slow-growing pathogenic species.

The outer membrane (OM) of bacteria like Escherichia coli and Shigella flexneri forms a barrier that protects cells against antibiotics and immune effectors. The surface-exposed leaflet is filled by lipopolysaccharides (LPS) decorated with long “O-antigen” (O-Ag) polysaccharides. The benefit of covering the surface with O-Ag is well appreciated; these long polysaccharides shield against host assaults. Our study reveals a hidden cost to these long O-Ag polysaccharides: transporting and assembling LPS modified with O-Ag compromises integrity of the OM antibiotic barrier, rendering bacteria vulnerable to antibiotics. Cells must balance O-Ag across two parameters—protection from the host and preserving OM integrity. Our findings also present an inherent benefit to not producing O-Ag, a common feature among diverse bacterial pathogens.

Bacteria must coordinate their growth rate, shape, and division to survive and flourish, yet how these cellular properties are maintained in the face of environmental stresses is poorly understood. Working with Escherichia coli , we show that activating the Rcs phosphorelay, an envelope stress-signaling system, in the absence of external stresses slows growth, shortens cells, and increases the concentration of the key division protein FtsZ, leading to more closely spaced division sites. Depleting the levels of IgaA, a regulator of the Rcs pathway, yielded similar phenotypes. However, activating Rcs via drug-induced cell-wall disruption did not affect growth rate, indicating that the physiological impact of this pathway depends on the context of activation. Our findings reveal links among cell growth, shape homeostasis, and cell envelope stress. Understanding this coupling further will provide new avenues to predict and modulate bacterial growth and physiology during stress.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains the world’s deadliest bacterial infection, in part because the bacterium’s unique cell envelope makes it highly resistant to antibiotics. Understanding how this protective barrier is built is essential for developing better treatments. In this study, we discovered that two previously uncharacterized lipoproteins help maintain the integrity of the mycobacterial cell envelope and contribute to drug resistance. Surprisingly, instead of acting as transport proteins as expected by structural similarity, these molecules regulate enzymes that assemble the bacterial envelope. This discovery highlights a previously unrecognized layer of control in envelope construction and opens new directions for targeting Mtb’s defenses with future therapies.

DD-peptidases, including carboxypeptidases and endopeptidases, are crucial for maintaining cell envelope homeostasis, with distinct roles for each enzyme in cell wall biogenesis and structural integrity. The enzymatic characterization presented in this study not only advances our understanding of fundamental Acinetobacter baumannii biology but also highlights these enzymatic activities as targets for the development of innovative therapeutic strategies to combat infections caused by this multidrug-resistant microbe.

Pseudomonas aeruginosa is an opportunistic bacterial pathogen that causes chronic infection in humans by forming protective, multicellular structures called biofilms. The strong natural resistance of bacterial biofilms to antibiotic and immune clearance presents a major therapeutic obstacle in P. aeruginosa disease management. As these structures often assemble on surfaces, i.e. host tissues or indwelling medical devices, the ability of P. aeruginosa to sense and respond to surface contact is a key step in initiating biofilm formation. We report that the Cpx signaling system in P. aeruginosa is activated upon surface attachment and operates independently of other known surface-sensing systems. Cpx responds to cellular stress, particularly disruptions to cell-surface proteins, suggesting that stress generated by bacterial surface adhesion is a relevant biofilm-inducing signal. These findings expand knowledge of surface-sensing mechanisms in P. aeruginosa and link surface recognition to a variety of other disease-related cellular processes regulated by the Cpx system.

Rural dwellings in Northwest China are typically self-built, lack energy-saving measures, and suffer from high energy consumption and poor thermal performance. Retrofitting building envelopes is a key strategy to improve energy efficiency and reduce carbon emissions. However, most existing studies focus on single-factor retrofits and single-objective evaluations, limiting their comprehensiveness and practical application. This study addresses these gaps by investigating single- and multi-factor retrofit scenarios for a typical rural house in Dingxi City of Northwest China. Using orthogonal experiments and DeST-h simulations, optimal combinations of envelope elements were identified, and the entropy method was applied to evaluate energy savings, incremental costs, cost-effectiveness, payback periods, and carbon-emission reductions. The results of the case show that exterior wall insulation is the most effective single-factor retrofit, achieving energy-saving rates of 45.79–48.46%, while roof insulation and additional sunspaces yield over 20% energy savings. Multi-factor retrofits significantly outperform single-factor schemes, with energy-saving rates ranging from 46.84 to 70.47%. The optimal retrofit solution includes 70 mm EPS boards for exterior walls, 80 mm XPS boards for roof thermal insulation, a window-to-wall ratio of 20%, broken-bridge aluminum hollow windows (6 + 12A + 6), and insulated glass for the sunspace. This study contributes to integrating energy, economic, and environmental dimensions, addressing the limitations of previous single-objective methods by developing a comprehensive evaluation framework. It also provides region-specific retrofit solutions tailored for the climatic and socioeconomic conditions of Dingxi City in Northwest China. These findings offer practical guidance for policymakers and practitioners to enhance energy efficiency and promote sustainable rural housing development.

The multilayered cell envelope of Gram-negative bacteria provides natural resistance to antibiotics. Understanding cell envelope synthesis and regulation is crucial for the identification of new antimicrobial targets and improved drug design. LpxC inhibitors, a new and promising class of antibiotics, impede function of the committed enzyme in lipopolysaccharide synthesis. Here, we characterize a new mechanism of resistance to the LpxC inhibitor PF-5081090, where the accumulation of lysophospholipids signals a reduction in cellular glycerophospholipid levels to repair outer membrane balance. This work proposes a new pathway to restore outer membrane asymmetry, which is a critical aspect of cell envelope integrity, and describes a role for lysophospholipids in bacterial cell signaling when lipopolysaccharide synthesis is disrupted.

The complex envelope of gram-negative bacteria is a critical structure. It is assembled and maintained by multiple essential pathways, all of which, including the β-barrel assembly machinery (BAM) complex, have been the focus of novel antibiotic discovery efforts. Species in the genus Klebsiella encode a paralog to the BAM complex component BamA, called BamK, but the importance and role of this protein has remained a mystery. Leveraging mutants resistant to a recently discovered BamA inhibitor, we describe how activation of the BaeSR envelope stress response system can activate bamK expression to overcome the loss of BamA or its function both in vitro and in vivo . These findings provide important insights into BamK, Klebsiella biology, gram-negative stress responses, and targeting outer membrane protein folding as an antibacterial strategy.