This review explains how two common lung bacteria in cystic fibrosis, Staphylococcus aureus and Pseudomonas aeruginosa, fight and help each other, and why the human antimicrobial peptide LL‑37 often can’t kill them. S. aureus can change into a tiny, slow‑growing form that resists antibiotics and LL‑37, while P. aeruginosa releases toxins that suppress S. aureus but also adapts its own defenses. The bacteria even protect each other from immune cells, making infections harder to clear.

Cystic fibrosis (CF) is an autosomal recessive genetic disorder that is characterized by recurrent and chronic infections of the lung predominantly by the opportunistic pathogens, Gram-positive <i>Staphylococcus aureus</i> and Gram-negative <i>Pseudomonas aeruginosa.</i> While <i>S. aureus</i> is the main colonizing bacteria of the CF lungs during infancy and early childhood, its incidence declines thereafter and infections by <i>P. aeruginosa</i> become more prominent with increasing age. The competitive and cooperative interactions exhibited by these two pathogens influence their survival, antibiotic susceptibility, persistence and, consequently the disease progression. For instance, <i>P. aeruginosa</i> secretes small respiratory inhibitors like hydrogen cyanide, pyocyanin and quinoline <i>N</i>-oxides that block the electron transport pathway and suppress the growth of <i>S. aureus</i>. However, <i>S. aureus</i> survives this respiratory attack by adapting to respiration-defective small colony variant (SCV) phenotype. SCVs cause persistent and recurrent infections and are also resistant to antibiotics, especially aminoglycosides, antifolate antibiotics, and to host antimicrobial peptides such as LL-37, human &#x3b2;-defensin (HBD) 2 and HBD3; and lactoferricin B. The interaction between <i>P. aeruginosa</i> and <i>S. aureus</i> is multifaceted. In mucoid <i>P. aeruginosa</i> strains, siderophores and rhamnolipids are downregulated thus enhancing the survival of <i>S. aureus</i>. Conversely, protein A from <i>S. aureus</i> inhibits <i>P. aeruginosa</i> biofilm formation while protecting both <i>P. aeruginosa</i> and <i>S. aureus</i> from phagocytosis by neutrophils. This review attempts to summarize the current understanding of the molecular mechanisms that drive the competitive and cooperative interactions between <i>S. aureus</i> and <i>P. aeruginosa</i> in the CF lungs that could influence the disease outcome.