The airways of patients with cystic fibrosis (CF) are highly complex, subject to various environmental conditions as well as a distinct microbiota. Pseudomonas aeruginosa is recognized as one of the most important pulmonary pathogens and the predominant cause of morbidity and mortality in CF. A multifarious interplay between the host, pathogens, microbiota, and the environment shapes the course of the disease. There have been several excellent reviews detailing CF pathology, Pseudomonas and the role of environment in CF but only a few reviews connect these entities with regards to influence on the overall course of the disease. A holistic understanding of contributing factors is pertinent to inform new research and therapeutics. In this article, we discuss the deterministic alterations in lung physiology as a result of CF. We also revisit the impact of those changes on the microbiota, with special emphasis on P. aeruginosa and the influence of other non-genetic factors on CF. Substantial past and current research on various genetic and non-genetic aspects of cystic fibrosis has been reviewed to assess the effect of different factors on CF pulmonary infection. A thorough review of contributing factors in CF and the alterations in lung physiology indicate that CF lung infection is multi-factorial with no isolated cause that should be solely targeted to control disease progression. A combinatorial approach may be required to ensure better disease outcomes. CF lung infection is a complex disease and requires a broad multidisciplinary approach to improve CF disease outcomes. A holistic understanding of the underlying mechanisms and non-genetic contributing factors in CF is central to development of new and targeted therapeutic strategies.

Gram-negative pathogens such as Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are the leading cause of nosocomial infections throughout the world. One commonality shared among these pathogens is their ubiquitous presence, robust host-colonization and most importantly, resistance to antibiotics. A significant number of two-component systems (TCSs) exist in these pathogens, which are involved in regulation of gene expression in response to environmental signals such as antibiotic exposure. While the development of antimicrobial resistance is a complex phenomenon, it has been shown that TCSs are involved in sensing antibiotics and regulating genes associated with antibiotic resistance. In this review, we aim to interpret current knowledge about the signaling mechanisms of TCSs in these three pathogenic bacteria. We further attempt to answer questions about the role of TCSs in antimicrobial resistance. We will also briefly discuss how specific two-component systems present in K. pneumoniae, A. baumannii, and P. aeruginosa may serve as potential therapeutic targets.

Topoisomerases are required for alleviating supercoiling of DNA during transcription and replication. Recent evidence suggests that supercoiling of bacterial DNA can affect bacterial pathogenicity. To understand the potential regulatory role of a topoisomerase I (TopA) in Pseudomonas aeruginosa, we investigated a previously isolated topA mutation using genetic approaches. We here report the effects of the altered topoisomerase in P. aeruginosa on type III secretion system, antibiotic susceptibility, biofilm initiation, and pyocyanin production. We found that topA was essential in P. aeruginosa, but a transposon mutant lacking the 13 amino acid residues at the C-terminal of the TopA and a mutant, named topA-RM, in which topA was split into three fragments were viable. The reduced T3SS expression in topA-RM seemed to be directly related to TopA functionality, but not to DNA supercoiling. The drastically increased pyocyanin production in the mutant was a result of up-regulation of the pyocyanin related genes, and the regulation was mediated through the transcriptional regulator PrtN, which is known to regulate bacteriocin. The well-established regulatory pathway, quorum sensing, was unexpectedly not involved in the increased pyocyanin synthesis. Our results demonstrated the unique roles of TopA in T3SS activity, antibiotic susceptibility, initial biofilm formation, and secondary metabolite production, and revealed previously unknown regulatory pathways.