NIH grant: Modulating the Action of Cylindrical Proteases to Eliminate Neisseria Gonorrhea and Chlamydia Trachomatis Infections (1R01AI192824-01A1)

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NIH grant 1R01AI192824-01A1: Modulating the Action of Cylindrical Proteases to Eliminate Neisseria Gonorrhea and Chlamydia Trachomatis Infections
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Martin Miguel Conda Sheridan. Award: $799619.
Start: 2026-06-18T00:00:00.
Project Summary/Abstract
 Sexually transmitted bacteria diseases caused by Chlamydia trachomatis (Ctr) and Neisseria gonorrhoeae (NG)
are the two most common sexually transmitted bacterial diseases. The infections caused by these pathogens
may result in infertility, ectopic pregnancy, blindness, and perinatal mortality. Over 1.70 M cases of chlamydia
and 0.65 M cases of drug-resistant gonorrhea are reported yearly in the US. Women with gonorrhea are co-
infected with chlamydia in 17.6%–57.9% of cases, while women with chlamydia are co-infected with gonorrhea
in 2.1%–17.2% of cases. These infections are treated with broad spectrum antibiotics, which can favor the
development of resistance on NG/CTr but also in other bacteria, or damage the microbiota, diminishing its
protective function and allowing bacteria and viruses to infect the patient. The Caseinolytic protease (ClpP)
proteolytic machinery regulates protein turnover and homeostasis and is key in bacterial growth and
development The machinery consists of the proteolytic unit (the ClpP) and its chaperone (ClpX), which
transports proteins to be degraded, and it is termed the ClpXP. Our theory is that molecules that inhibit the
action of the ClpX chaperone can become efficient antibacterial agents against both pathogens. We have
found that the dihydrothiazepines can erradicate both pathogens and prevent the action of the ClpXP
complex. Our goal is to advance the dihydrothiazepines as selective agents against Ctr and NG infections. To
develop these therapeutic agents, we have envisioned four specific aims. Specific Aim 1. Synthesis
and Optimization of the Pharmacophore. Our goal is to use computational models to design
dihydrothiazepines molecule that will be synthesized, purified, and characterized using chemical techniques.
The molecules will be tested against Ctr and NG and their toxicity against human cells evaluated. Also, we will
determine their effect in other bacterial, including those from the microbiota. Specific Aim 2. Assessment
of Stability and In Vivo Activity. We will study the stability of the most active molecules under various
conditions. Then, we will study the pharmacokinetics, biodistribution , and antibacterial activity against Ctr and
NG in mice. Specific Aim 3. Target Validation and Effect. We will study the ability of the compounds to
inhibit the activity of ClpX using a luciferase assay and to block protein degradation. We will try grow crystal of
the protein and the molecule and will study if the molecules prevent the assembly of the ClpXP system. Finally,
we will assess the ability of the bacteria to develop resistance to the molecules.

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