A major problem in the antimicrobial field is limited treatment options for infections caused by Gram-negative bacteria. Gram-negative pathogens exhibit innate resistance against many antibiotics due to their highly drug-impermeable outer membrane, which limits access to intracellular drug targets. In addition, Gram-negative bacteria, particularly in hospital-acquired infections, exhibit high rates of acquired drug resistance. In contrast, Gram-positive pathogens are generally more easily killed due to differences in cell membrane composition and structure. Given the scarcity of new antibiotics in the pharmaceutical pipeline and waning efficacy of existing drugs for Gram-negative infections, new therapeutic strategies must be developed to address this clinical gap.

In recent work (in press at ACS Infectious Disease), we developed a membrane-disruptive antibiotic adjuvant to rescue the activity of poorly-penetrating antibiotics. For this, we leveraged the affinity of cationic, amphipathic peptides for the negatively-charged bacterial membrane and engineered multivalent constructs with more potent membrane-disruptive activity. We showed that co-delivery of multivalent peptide constructs with antibiotics were able to sensitize drug-resistant clinical isolates of P. aeruginosa to antibiotics that are generally inactive in Gram-negative bacteria (i.e. narrow-spectrum antibiotics). Using this approach, we were able to broaden the spectrum of existing antibiotics.

In other recent work published in Nanoscale Horizon, an alternative broad-spectrum therapy was developed. Rather than target bacteria directly, we targeted hyperinflammation from the host response to infection, which can lead to mortality via tissue/organ damage. We demonstrated that infection-associated inflammation can be dampened via delivery of siRNA targeting an interferon regulatory factor to macrophages in lung infection mouse models. Using a nanoparticle delivery system, we were able to protect the siRNA cargo from degradation after systemic delivery and direct siRNA accumulation in macrophages via surface display of macrophage-targeting peptides on the nanoparticles. This treatment resulted in improved survival rate for both Gram-negative and Gram-positive infection models.


L. W. Chan, K. E. Hern, C. Ngambenjawong, K. Lee, E. J. Kwon, D. T. Hung, S. N. Bhatia. Selective permeabilization of Gram-negative bacterial membranes using multivalent peptide constructs for antibiotic sensitization. ACS Infect. Dis. 7, 721-732 (2021).

B. Kim, Q. Yang, L. W. Chan, S. N. Bhatia, E. Ruoslahti, M. J. Sailor. Fusogenic porous silicon nanoparticles as a broad-spectrum immunotherapy against bacterial infections. Nanoscale Horiz. 6, 330-340 (2021).