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Omp26 as a Macrolide Synergistic Target against Nontypeable Haemophilus influenzae

Award Number: F31AI197842
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 10/15/2026
PERIOD OF PERFORMANCE END DATE: 10/14/2027

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Omp26 as a Macrolide Synergistic Target against Nontypeable Haemophilus influenzae - PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is characterized by decreased lung function and increased inflammation, punctuated by periods of increased coughing and shortness of breath known as exacerbations. Exacerbated COPD results in not only a hastening of lung decline but also a decline in the quality of life and mental health of patients. The obligate human pathogen nontypeable Haemophilus influenzae (NTHi) is the primary cause of exacerbated COPD, responsible for a minimum of ~30% of all exacerbations. The macrolides azithromycin and clarithromycin are predominantly prescribed to treat NTHi-complicated COPD due to its broad activity and immunomodulatory effects that decrease inflammation and the prevalence of future exacerbations. However, due to intrinsic factors and acquired mutations, macrolide treatment is becoming less effective against this bacterial pathogen. The primary objective of this proposal is to optimize the current treatment method for NTHi-exacerbated COPD by addressing established macrolide resistance and the ability to gain macrolide resistance while maintaining the benefits of macrolides. We performed a Tn-Seq screening to identify genes necessary for intrinsic resistance to clarithromycin and cross-referenced the results with those of another screening our lab performed for genes necessary for infection in the murine lung to explore the idea that drugs targeting proteins with dual requirements for both conditions would restore sensitivity to resistant strains and would constrain potential escape mutations. We characterized the gene encoding for the outer membrane protein Omp26, homolog of the E. coli periplasmic chaperone Skp, and found that deletion of omp26 resulted in susceptibility to clarithromycin in strains overexpressing the macrolide efflux pump AcrAB and that Omp26 plays a role in resistance to the human complement system. I hypothesize that targeting macrolide intrinsic resistance factor Omp26 in NTHi can be exploited to make NTHi more sensitive to macrolides and to host immune clearance mechanisms and potentially restore macrolide sensitivity to resistant strains. Experiments proposed in Aim 1 will investigate the function of Omp26 by defining its role in serum resistance, examining how it contributes to the composition of outer membrane proteins, and performing a survey of the necessity of Omp26 for infection in the murine lung across multiple strains of NTHi. Aim 2 will address the effect Omp26 has on major lung virulence associated phenotypes including heavy metal resistance, acquisition of host-sequestered nutrients, and resistance to oxidative stress. Finally, the experiments proposed in Aim 3 will determine the efficacy of targeting Omp26 in macrolide resistant clinical NTHi isolates with ribosomal mutations. Collectively, this data will contribute to further studies in the role periplasmic chaperones play in virulence and provide the framework necessary for the designing of in vitro assays based on the identified mechanisms of Omp26 to screen for future drugs for the treatment of nontypeable H. influenzae-exacerbated COPD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $50,114 )
2026	2026	UNIVERSITY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Allergy and Infectious Diseases Research	000	1	4/17/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Omp26 as a Macrolide Synergistic Target against Nontypeable Haemophilus influenzae

Award Number: F31AI197842

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 10/15/2026

PERIOD OF PERFORMANCE END DATE: 10/14/2027

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