Mechanism of the signal transduction across the bacterial cell envelope

The National Institute of Allergy and Infectious Diseases, part of the Department of Health and Human Services, awarded $687,817 to the University of Texas Health Science Center at Houston on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate bacterial cell envelope signal transduction mechanisms relevant to antibiotic resistance.

The recipient will conduct research to elucidate how the regulator of capsule synthesis (RCS) stress response monitors outer membrane integrity and promotes outer membrane homeostasis in gram-negative bacteria. Using genetic analysis, in vitro and in vivo biochemical approaches, and molecular dynamics simulations, the research team will identify the molecular signal and mechanism that activates the sensory protein RcsF and determine how stress signals are transduced across the multilayered cell envelope. This work addresses how bacterial envelope stress responses confer intrinsic resistance to antibiotics, cationic antimicrobial peptides, and other biological agents. Understanding RCS-mediated resistance mechanisms may facilitate antibiotic discovery and improve clinical outcomes against gram-negative pathogens.

The award funds research at the University of Texas Health Science Center at Houston in Houston, Texas from September 1, 2026 through August 31, 2027. The University of Texas System, the parent organization, holds substantial federal grant authority that flows through to affiliated health centers. This is a Project Grant, which funds discrete research projects under the NIH assistance type structure.

Abstract

Antibiotic resistance is an urgent threat to public health, particularly among gram-negative bacteria, due to their multilayered cell envelope structure, which includes the outer membrane (OM). The OM outer leaflet is composed of lipopolysaccharide (LPS) molecules that make the OM impermeable to various compounds, including clinically used antibiotics. Our long-term goal is to gain a comprehensive understanding of how bacteria build and maintain homeostasis of the OM to aid antibiotic discovery. Bacterial envelope stress responses are signal transduction pathways that confer significant intrinsic resistance to antibiotics, immune factors, and other biological agents targeting the envelope. They achieve this by mitigating damage and inhibiting the penetration or activity of these agents. Despite their importance, the molecular signals and activation mechanisms of stress responses remain poorly understood because of the complexity of envelope biogenesis. This proposal aims to elucidate how the regulator of capsule synthesis (RCS) stress response monitors OM integrity and promotes OM homeostasis. RCS is one of the most complex stress responses in bacteria and can transduce the stress signal from the cell surface to the cytoplasm. Disruptions in the LPS layer at the cell surface, including those caused by cationic antimicrobial peptides (camps) and last-resort antibiotics like polymyxin b, have long been known to strongly activate RCS. Through genetic analysis, in vitro and in vivo biochemical approaches, and molecular dynamics simulations, we aim to identify the molecular signal and mechanism that activates the sensory protein rcsf, and determine how the stress signal is transduced across the multilayered cell envelope. Through our research, we will provide a mechanistic understanding of the well-established role of RCS in resisting camps, and facilitate studies on the role of RCS in immune evasion, host survival, and pathogenesis. More broadly, studies of RCS will provide a new mechanistic paradigm for a potentially widely utilized mechanism of envelope stress responses and how bacteria use them to promote antibiotic resistance.