Insights into the antibacterial mechanism of PEGylated nano-bacitracin A against Streptococcus pneumonia: both penicillin-sensitive and penicillin-resistant strains

BACKGROUND: Multidrug-resistant (MDR) Streptococcus pneumonia constitute a major worldwide public health concern. MATERIALS AND METHODS: In our preliminary study, PEGylated nano-self-assemblies of bacitracin A (PEGylated Nano-BA(12K)) showed strong antibacterial potency against reference S. pneumonia strain (ATCC 49619). In this study, the possibility of applying PEGylated Nano-BA(12K) against penicillin-resistant S. pneumonia was further investigated. In addition, the underlying antibacterial mechanism of PEGylated Nano-BA(12K) against both sensitive and resistant S. pneumonia was also clarified systematically, since S. pneumonia was naturally resistant to its unassembled counterpart bacitracin A (BA). RESULTS: PEGylated Nano-BA(12K) showed strong antibacterial potency against 13 clinical isolates of S. pneumonia, including five penicillin-resistant strains. Structural changes, partial collapse, and even lysis of both penicillin-sensitive and penicillin-resistant bacteria were observed after incubation with PEGylated Nano-BA(12K) via transmission electron microscopy and atomic force microscopy. Thus, the cell wall or/and cell membrane might be the main target of PEGylated Nano-BA(12K) against S. pneumonia. PEGylated Nano-BA(12K) exhibited limited effect on the permeabilization and peptidoglycan content of cell wall. Surface pressure measurement suggested that PEGylated Nano-BA(12K) was much more tensioactive than BA, which was usually translated into a good membranolytic effect, and is helpful to permeabilize the cell membrane and damage membrane integrity, as evidenced by depolarization of the membrane potential, permeabilization of membrane and leakage of calcein from liposomes. CONCLUSION: Collectively, great cell membrane permeability and formidable membrane disruption may work together for the strong antibacterial activity of PEGylated Nano-BA(12K) against S. pneumonia. Taken together, PEGylated Nano-BA(12K) has excellent potential against both penicillin-sensitive and penicillin-resistant S. pneumonia and might be suitable for the treatment of S. pneumonia infectious diseases.