The susceptibility of paired mucoid and nonmucoid variants of Pseudomonas aeruginosa isolated from 13 patients with cystic fibrosis (CF) to killing by a 55,000-Da bactericidal protein (BP55) from human polymorphonuclear leukocytes was studied. Mucoid and nonmucoid variants were equally sensitive to killing by BP55 at both pH 5.6 and pH 7.2. Eleven of the isolates were resistant to the bactericidal activity of 10% normal human serum but were as sensitive as the serum-sensitive isolates to BP55. Similarly, the 15 isolates with lipopolysaccharides (LPS) containing O-polysaccharide side chains (smooth LPS) were as sensitive to BP55 as those isolates with rough LPS. P. aeruginosa isolates from patients in poor clinical condition were more likely to have LPS of the smooth type and to be resistant to killing by 10% human serum than the isolates from patients in good clinical condition. We have concluded that the susceptibility of the P. aeruginosa isolates from patients with CF to killing by BP55 does not correlate with mucoid or nonmucoid variations, with the presence or absence of smooth LPS, or with the sensitivity or resistance to killing by normal human serum.Cystic fibrosis (CF) is an inherited autosomal disease characterized by frequent pulmonary infections with Pseudomonas aeruginosa (1). The clinical condition of the patient with CF deteriorates with the appearance of mucoid colonial forms which emerge in addition to the original nonmucoid P. aeruginosa colonizer (10). Despite aggressive multiple antibiotic therapy, P. aeruginosa often persists in the respiratory tract because of its characteristic resistance to a broad range of antibiotics. A naturally occurring antibacterial protein with remarkable potency against P. aeruginosa has been isolated from the cytoplasmic granules of human polymorphonuclear leukocytes (PMN) (15). This 55,000-Da bactericidal protein (BP55) binds to the target bacteria and depolarizes the cytoplasmic membrane, which results in the cessation of amino acid transport and eventual cell death (16). Like the 57,000-Da cationic antimicrobial protein (CAP57) and the 59,000-Da bactericidal and permeabilityincreasing protein (B/PI), which bind to the lipopolysaccharides (LPS) from the outer membranes of Salmonella typhimurium and Escherichia coli (31, 37), respectively, BP55 binds to the LPS from P. aeruginosa (14,35).The outermost portion of the LPS, the O-polysaccharide side chain, plays an important role in the pathogenicity of most gram-negative bacteria, including P. aeruginosa (4, 23). O-polysaccharide side chains of smooth LPS can sterically hinder the formation of the complement membrane attack complex, thus conferring serum resistance to the bacteria (8, 17). The smooth LPS can also confer resistance to 3-lactam antibiotics (7). Similarly, the resistance of S. typhimurium and E. coli to the antimicrobial proteins of PMN, CAP57 and B/PT, increases with the length of the 0 polysaccharides of LPS (6,38). The relationship between the susceptibility of P. aeruginosa to antibacterial protei...