Overview: Microbial Interactions in Polymicrobial Lung Infections
In chronic lung diseases such as COPD, cystic fibrosis, and COPD-related bronchial infections, microbial communities often comprise multiple species whose interactions determine disease trajectory and treatment outcomes. Polymicrobial infections can amplify virulence and antibiotic resistance, complicating management. This evolving field recognizes that even low-abundance microbes can steer the behavior of dominant pathogens, underscoring the need to understand interspecies dynamics when selecting antibiotics.
Study Focus: Pseudomonas aeruginosa and Streptococcus salivarius
Researchers isolated Pseudomonas aeruginosa and Streptococcus salivarius from bronchial samples of COPD patients to investigate how antibiotic treatment, specifically aztreonam, modulates interbacterial relationships. By examining lasR-intact and lasR-mutant P. aeruginosa strains alongside corresponding S. salivarius isolates, the study explored static and dynamic interactions, transcriptomic changes, and functional outcomes in the presence of a sub-inhibitory aztreonam concentration.
Key Findings: Aztreonam Can Rebalance Competition
On antibiotic-free media, P. aeruginosa typically dominates mixed cultures, replicating its robust quorum-sensing (QS) systems. However, at 8 µg/mL aztreonam—sub-inhibitory for P. aeruginosa—the dynamics shift. S. salivarius gains a competitive edge and can invade P. aeruginosa colonies, reversing the usual competitive hierarchy. This shift is particularly evident in dynamic “bacterial game” experiments where the initial ratio does not dictate the final outcome under aztreonam exposure.
Mechanisms: QS Gene Suppression and Cross-Feeding Effects
Extracellular products from S. salivarius suppress QS-regulated virulence genes and key regulators in P. aeruginosa, including lasR, rhlR, and mvfR, as well as genes involved in pyocyanin biosynthesis. Transcriptomic analyses reveal broad downregulation of QS networks and metabolic pathways in P. aeruginosa when S. salivarius supernatants are present, with stronger effects under aztreonam treatment. In contrast, aztreonam can activate S. salivarius in co-culture, upregulating growth and biosynthetic pathways that support its competitive expansion against P. aeruginosa.
Cross-Feeding Dynamics
Cross-feeding experiments using a 0.22 µm membrane show that aztreonam can enable S. salivarius to harness interspecies metabolic exchange. In co-culture, S. salivarius upregulates hundreds of genes related to translation, transcription, and macromolecule production, while P. aeruginosa experiences suppressed QS and metabolic activity. The net effect is a context-dependent rebalancing of interspecies interactions that favors suppression of P. aeruginosa virulence when aztreonam is present.
<h2 Functional Outcomes: Virulence Reduction and Host Benefit
Pyocyanin production by P. aeruginosa declines in the presence of S. salivarius extracellular products, particularly under aztreonam exposure. In vivo validation using a Caenorhabditis elegans model shows reduced P. aeruginosa lethality when aztreonam or S. salivarius supernatants are applied, with the strongest protection observed during combined aztreonam and S. salivarius exposure. These findings suggest that aztreonam not only inhibits P. aeruginosa directly but also modulates interspecies interactions to dampen overall virulence.
<h2 Clinical Implications: Rethinking Antibiotic Strategies in COPD
The study highlights a critical concept: antibiotic efficacy in polymicrobial infections extends beyond single-pathogen suppression. Sub-inhibitory antibiotic concentrations can recalibrate microbial communities, enabling beneficial interactions with resident commensals such as S. salivarius. In COPD-associated infections, incorporating knowledge of interspecies dynamics could influence antibiotic choice, dosing strategies, and adjunctive therapies aimed at promoting a healthier lung microbiome while restraining opportunistic pathogens like P. aeruginosa.
Future Directions
Further work should investigate the generalizability of aztreonam-mediated recalibration across diverse P. aeruginosa strains and oral streptococci, including in vivo models that mimic chronic lung environments. Dissecting the molecular mediators of S. salivarius’ anti-P. aeruginosa activity and identifying transferable antimicrobial peptides or biosynthetic products could inform novel therapeutic approaches that complement conventional antibiotics.
