Bacterial protein compositions and uses thereof
Inventors
Rather, Philip • Weiss, David • Chin, Chui-Yoke • Tipton, Kyle
Assignees
Emory University • US Department of Veterans Affairs
Publication Number
US-11291712-B2
Publication Date
2022-04-05
Expiration Date
2038-09-19
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Abstract
Disclosed herein is an attenuated Acinetobacter baumannii comprising an expression vector comprising a nucleic acid encoding the ABUW_1645 protein or a variant thereof. Disclosed herein are methods of treating or preventing colonization, infection, or disease by an Acinetobacter baumannii microbe, the method comprising administering a clinically effective dose of the attenuated Acinetobacter baumannii to a subject in need thereof, wherein the attenuated Acinetobacter baumannii comprises an expression vector expressing the ABUW_1645 protein or variants thereof.
Core Innovation
The invention discloses an attenuated Acinetobacter baumannii comprising an expression vector that includes a nucleic acid encoding the ABUW_1645 protein or a variant thereof. The ABUW_1645 protein acts as a master regulator controlling phenotypic switching between a highly virulent opaque phenotype (VIR-O) and an avirulent translucent phenotype (AV-T) in A. baumannii. Overexpression of ABUW_1645 locks the bacteria in the less virulent translucent state, which exhibits attenuated virulence and increased susceptibility to host innate immune defenses, hospital disinfectants, and desiccation.
The problem addressed by the invention arises from the significant healthcare threat posed by Acinetobacter baumannii, noted for causing hospital and community-acquired infections with high antibiotic resistance and virulence. Its ability to persist under harsh hospital conditions, including resistance to disinfectants and desiccation, and the unclear molecular mechanisms controlling its virulence and survival, complicate treatment and infection control.
The invention solves this problem by harnessing the regulatory mechanism controlling the phenotypic switch via expression of the ABUW_1645 protein. By administering attenuated A. baumannii expressing ABUW_1645 or its variants, the bacteria are maintained in or induced into the avirulent phenotype, thereby preventing or treating infections. This approach provides a live attenuated vaccine that protects subjects from lethal challenges with virulent A. baumannii and can be used therapeutically or prophylactically, including in combination with antibiotics.
Claims Coverage
The patent presents six main inventive features related to methods and compositions involving attenuated Acinetobacter baumannii expressing the ABUW_1645 protein or its variants for vaccination, treatment, and prevention of infection.
Method of vaccinating against Acinetobacter baumannii
Administering an Acinetobacter baumannii comprising an expression vector encoding the ABUW_1645 protein (SEQ ID NO: 1) to a subject in need thereof.
Method of treating Acinetobacter baumannii infection
Administering an Acinetobacter baumannii comprising an expression vector encoding the ABUW_1645 protein (SEQ ID NO: 1) to a subject in need thereof.
Method of combination therapy
Administering the Acinetobacter baumannii expressing ABUW_1645 in combination with one or more antibiotics or antimicrobial agents, specifically imipenem, meropenem, or colistin.
Method of treating colonization, infection, or disease with attenuated bacteria
Administering a clinically effective dose of an attenuated Acinetobacter baumannii expressing the ABUW_1645 protein (SEQ ID NO: 1) to a subject in need to treat or prevent colonization, infection, or disease.
Oral administration of attenuated bacteria
Administering the attenuated Acinetobacter baumannii expressing ABUW_1645 orally.
Use of live attenuated Acinetobacter baumannii
Administering the attenuated Acinetobacter baumannii expressing ABUW_1645 as a live attenuated bacteria.
The claims cover methods of vaccination and treatment of Acinetobacter baumannii infections using attenuated bacteria expressing the ABUW_1645 protein or its variants, alone or in combination with antibiotics, with specific provisions for oral and live attenuated administration.
Stated Advantages
Overexpression of ABUW_1645 locks A. baumannii in a translucent, avirulent phenotype resulting in drastically reduced virulence.
The attenuated bacteria expressing ABUW_1645 confer protection as a live attenuated vaccine against lethal infection.
VIR-O cells exhibiting virulence are resistant to host innate immune antimicrobials as well as hospital disinfectants and desiccation, highlighting the importance of the phenotypic switch.
Targeting the phenotypic switch provides a novel approach to prevent infections and control bacterial persistence in hospital environments.
Documented Applications
Vaccination against Acinetobacter baumannii infections in subjects by administering attenuated A. baumannii expressing ABUW_1645 or variants.
Treatment of Acinetobacter baumannii infections by administering attenuated A. baumannii expressing ABUW_1645, optionally in combination with antibiotics such as imipenem, meropenem, or colistin.
Prevention or reduction of colonization or infection of Acinetobacter baumannii in subjects at risk.
Use of live attenuated Acinetobacter baumannii expressing ABUW_1645 as a vaccine or therapeutic agent.
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