Bioengineered Nisin A Derivatives Display Enhanced Activity against Clinical Neonatal Pathogens

Abstract

Neonatal infection is a significant cause of mortality and morbidity in infants. The global incidence of multi-drug resistance continues to rise among neonatal pathogens, indicating a need for alternative treatment strategies. Nisin is an antimicrobial peptide that exhibits broad-spectrum activity against a wide variety of clinical pathogens and can be used in combination with antibiotics to improve their effectiveness. This study examined the activity of nisin and bioengineered derivatives against multi-drug resistant Streptococcus agalactiae and Staphylococcus capitis isolates and investigated the potential synergy between nisin peptides and selected antibiotics. Whole genome sequence analysis of the strains revealed the presence of multi-drug resistant determinants, e.g., macrolide, tetracycline, β-lactam, aminoglycoside, while the S. agalactiae strains all possessed both nsr and nsrFP genes and the S. capitis strains were found to encode the nsr gene alone. Deferred antagonism assays demonstrated that nisin PV had improved antimicrobial activity against all strains tested (n = 10). The enhanced specific activity of this peptide was confirmed using minimum inhibitory concentrations (MIC) (0–4-fold lower MIC for nisin PV) and broth-based survival assays. Combinations of nisin peptides with antibiotics were assessed for enhanced antimicrobial activity using growth and time-kill assays and revealed a more effective nisin PV/ampicillin combination against one S. capitis strain while a nisin A/erythromycin combination displayed a synergistic effect against one S. agalactiae strain. The findings of this study suggest that nisin derivatives alone and in combination with antibiotics have potential as alternative antimicrobial strategies to target neonatal pathogens.

Engineering of Nisin as a Means for Improvement of Its Pharmacological Properties: A Review

“…Pores are formed by the C-terminal fragment of this antibiotic (amino acids 23–34, rings D and E, see Figure 1 ) and are believed to cause rapid dissipation of transmembrane electrostatic potential, which in turn results in membrane permeabilization and rapid bacterial cell death. Although quite limited, studies on bioengineering of this fragment provided some valuable variants of improved solubility at neutral pH [ 37 ], resistance to the specific immunity system present in some bacteria [ 38 ] or of increased antibacterial activity [ 39 , 40 , 41 ].…”

“…Advanced, highly sensitive solid-state NMR study on binding of nisin to lipid II present in a model membrane consisting of mixture of artificial phospholipids brought identification of Ile4, Lys12, Ser 29 and the whole hinge region as functional hotspots that are critical for the cellular adaptability of nisin [ 46 ]. Indeed, in a series of double and triple mutants those derived from mutations of at least two of these hotspots exerted the highest antibacterial activity [ 40 , 42 , 47 , 48 ]. One of them displayed promising activity against Listeria monocytogenes [ 48 ], a Gram-positive strain that causes listeriosis, an invasive disease affecting pregnant women, neonates, the elderly, and immunocompromised individuals.…”