Resisting resistance with PAF receptor antagonists

Abstract

Bacterial resistance to antibiotics is a growing and serious problem. Since the advent of effective modern antibacterial therapy, death and morbidity associated with bacterial infection have become so unusual that the efficacy of antibiotics has at times been taken for granted. However, a relaxed attitude to this problem is not warranted because the consequences of increasing and widespread antibiotic resistance are likely to be dramatic and sudden. It is therefore imperative that research continues to establish mechanisms of bacterial resistance with the hope that such understanding will provide new avenues for an effective approach to this problem.The production of a thick layer of mucus in the airways can provide protection for infectious organisms from antibiotics and this can be particularly serious in cystic fibrosis patients who, as a result of prolonged and ineffective antibiotic therapy, can find themselves suffering from infections resistant to a wide range of antibacterial agents. Lemjabbar and Basbaum [1xPlatelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. Lemjabbar, H. and Basbaum, C. Nat. Med. 2002; 8: 41–46Crossref | PubMed | Scopus (253)See all References[1] have investigated the mechanisms of mucin production in response to Staphylococcus aureus and shown that a direct interaction between the bacterial cell wall constituent lipoteichoic acid (LTA) and the platelet-activating factor (PAF) receptor is a crucial event in the initiation of a signaling cascade resulting in the production of mucin.Using a human epithelial cell line stably transfected with a construct consisting of the MUC2 gene and luciferase as a reporter, they have shown that S. aureus, PAF and LTA can induce expression of the gene and that this response can be inhibited by antagonists of the PAF receptor. They have also shown that the role of the activation of the G-protein-coupled PAF receptor is to activate the disintegrin and metalloproteinase ADAM10, which is then responsible for cleaving heparin-binding epidermal growth factor (HB-EGF) and the consequent transactivation of the EGF receptor. Gram-negative lipopolysaccharide has previously been shown to induce mucin production via a Ras–NF-κB (nuclear factor κB) signaling axis. The present study shows that activation of the EGF receptor also feeds into this pathway having similar results.Despite an apparently minor role in thrombosis and hemostasis, PAF gained its name following the observation that it activates platelets. Its subsequent identification as an inflammatory mediator resulted in the evaluation of many PAF receptor antagonists in a variety of clinical circumstances including asthma, sepsis and pancreatitis. However, clinical results have been disappointing and, to date, no PAF receptor antagonist is in clinical use. The results of this study suggest that the PAF receptor might be of clinical importance after all, although activated not by the endogenous ligand but by a molecular mimic of PAF, LTA.These data hint at the possibility that treatment of severe respiratory infections with a combination of antibiotics and PAF receptor antagonists might not only increase the overall efficacy of the treatment but might also help to minimize the development of bacterial resistance. If true, this could be a welcome and relatively straightforward addition to the antibacterial arsenal of drugs that might help us keep one step ahead in the battle with bacterial infection.