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Cystic fibrosis (CF) is the most common life-threatening genetic disease among Caucasians. CF patients suffer from chronic lung infections due to the presence of thick mucus, caused by cftr gene dysfunction. The two most commonly found bacteria in the mucus of CF patients are Staphylococcus aureus and Pseudomonas aeruginosa. It is well known that early-infecting P. aeruginosa strains produce anti-staphylococcal compounds and inhibit S. aureus growth. More recently, it has been shown that late-infecting P. aeruginosa strains develop commensal-like/coexistence interaction with S. aureus. The aim of this study was to decipher the impact of P. aeruginosa strains on S. aureus. RNA sequencing analysis showed 77 genes were specifically dysregulated in the context of competition and 140 genes in the context of coexistence in the presence of P. aeruginosa. In coexistence, genes encoding virulence factors and proteins involved in carbohydrates, lipids, nucleotides and amino acids metabolism were downregulated. On the contrary, several transporter family encoding genes were upregulated. In particular, several antibiotic pumps belonging to the Nor family were upregulated: tet38, norA and norC, leading to an increase in antibiotic resistance of S. aureus when exposed to tetracycline and ciprofloxacin and an enhanced internalization rate within epithelial pulmonary cells. This study shows that coexistence with P. aeruginosa affects the S. aureus transcriptome and virulence.

The NorA efflux pump lowers intracellular fluoroquinolone concentrations by expelling antibiotics through the membrane of Staphylococcus aureus. We identified 3-aryl-4-methyl-2-quinolin-2-ones as compounds able to restore the activity of the NorA substrate, ciprofloxacin, against resistant S. aureus strains, and acting as efflux pump inhibitors (EPI). In particular, 5-hydroxy-7-methoxy-4-methyl-3-phenylquinolin-2-one (6 c) presents both an EPI and an antimicrobial effect. Its efficacy and safety make it a potential candidate for further investigations., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This study provides insight into the antibacterial activity of the cytotoxic nucleoside analogue gemcitabine against clinical multiresistant Staphylococcus aureus strains. Classical methods were used for determination of the minimum inhibitory concentration (MIC) and synergy in vitro, and polymerase chain reaction (PCR) products were sequenced to search for mutations in nucleoside kinase genes in resistant strains. Gemcitabine and its derivative CP-4126 were effective against meticillin-susceptible S. aureus (MSSA), meticillin-resistant S. aureus (MRSA) and glycopeptide-intermediate S. aureus (GISA) isolates, with MICs ranging between 0.06 mg/L and 4.22 mg/L. Bactericidal activity was shown in time-kill studies as well as synergy with gentamicin. Mutations in the nucleoside kinase gene SadAK were observed in resistant strains, indicating a role for this enzyme in gemcitabine activity. Nucleoside analogues have antimicrobial activity and these results could be used for further identification and development of new antibiotics., (Copyright © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Cystic fibrosis (CF) is a serious genetic disease that leads to premature death, mainly due to impaired lung function. CF lungs are characterized by ongoing inflammation, impaired immune response, and chronic bacterial colonization. Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA) are the two most predominant bacterial agents of these chronic infections. Both can colonize the lungs for years by developing host adaptation strategies. In this review, we examined the mechanisms by which SA and PA adapt to the host immune response. They are able to bypass the physical integrity of airway epithelia, evade recognition, and then modulate host immune cell proliferation. They also modulate the immune response by regulating cytokine production and by counteracting the activity of neutrophils and other immune cells. Inhibition of the immune response benefits not only the species that implements them but also other species present, and we therefore discuss how these mechanisms can promote the establishment of coinfections in CF lungs. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus (SA) is the major colonizer of the lungs of cystic fibrosis (CF) patients during childhood and adolescence. As patients age, the prevalence of SA decreases and Pseudomonas aeruginosa (PA) becomes the major pathogen infecting adult lungs. Nonetheless, SA remains significant and patients harboring both SA and PA are frequently found in the worldwide cohort. The overall impact of co-infection remains controversial. Furthermore, co-infecting isolates may compete or coexist. The aim of this study was to analyse if co-infection and the coexistence of SA and PA could lead to worse clinical outcomes. The clinical and bacteriological data of 212 Lyon CF patients were collected retrospectively, and patients were ranked into three groups, SA only (n = 112), PA only (n = 48) or SA plus PA (n = 52). In addition, SA and PA isolates from co-infected patients were tested in vitro to define their interaction profile. Sixty five percent (n = 34) of SA/PA pairs coexist. Using univariate and multivariate analysis, we confirm that SA patients have a less severe clinical condition than others, and PA induces a poor outcome independently of the presence of SA. Regarding co-infection, no significant difference in clinical outcomes was observed between patients with coexisting pairs and patients with competitive pairs. However, when compared to SA mono-infected patients, patients with coexisting pair presented higher frequency and length of hospitalizations and more exacerbations. We suggest that coexistence between SA and PA may be an important step in the natural history of lung bacterial colonization within CF patients. [ABSTRACT FROM AUTHOR]