Fit and resistant is a worst case scenario with bacterial pathogens.

Pseudomonas aeruginosa is a prevalent nosocomial pathogen (1) and a threat in neonatal and intensive care units, causing deadly infections in ventilator-associated pneumonia or immunosuppressed patients. P. aeruginosa strains causing these infections are frequently multiresistant, and treatment is a nightmare for clinicians (2). P. aeruginosa colonizing the lungs of cystic fibrosis patients cannot be eradicated even after intensive antibiotic therapy. Combinatorial therapies make use of β-lactams, colistin, fluoroquinolone, or aminoglycosides, but resistance to these drugs keeps emerging at high rate, except for colistin. The acquisition of resistance happens via mutations or acquisition of new functions by horizontal gene transfer. The downside for bacteria acquiring resistance is a pay back in fitness cost. Antibiotics target vital cell functions, such as protein synthesis, DNA supercoiling, or integrity of the cell envelope, and compensatory mutations may result in these features not being reliable (3). This is good news and suggests that once the selective pressure of antibiotic treatment ceased, the resistant strains could be outcompeted by strains that are not resistant but fitter, which will be a stumbling block to the spread of multiresistant organisms. However, the work by Skurnik et al. in PNAS (4) demonstrates that a gain of in vivo fitness by P. aeruginosa is due to the lack of the outer membrane protein OprD, and this event correlates acquisition of carbapenem resistance. What are the usual mechanisms that preserve bacteria from the killing/stasis impact of antibiotics? Resistance can result from the enzymatic modification/degradation of the drug itself such as with P. aeruginosa strains that encode β-lactamases. Resistance can result from modification of the drug target, such as a mutation in the housekeeping RNA polymerase, which is no longer inhibited by rifampicin. However, an important mechanism, which relates to the study by Skurnik et al. (4), is associated with the permeability of the outer membrane of Gram-negative bacteria. This hydrophobic barrier restricts the diffusion of toxic compounds into the cell. Nevertheless, bacteria have channels, called outer membrane proteins (OMPs), through which small molecules diffuse passively, thus preserving exchange with the milieu. Some channels are nonspecific, and the selectivity is based on the size of the molecule and not on its nature. OprF is a major P. aeruginosa porin, which allows diffusion of small ions or small polar nutriments but does not allow a high rate of diffusion because a large number of the OprF porins are in a close conformation. As a result, the overall permeability of the P. aeruginosa outer membrane is restricted. Other porins display specificity. OprP is a phosphate-specific porin, OprB is a glucose/carbohydratespecific porin, and OprC is likely involved in copper transport (5). Several P. aeruginosa OMPs, e.g., OprM, OprN, and OprJ, have a role in the efflux of toxic compounds. Each of these OMPs assembles into a tripartite supramolecular complex (e.g., MexAB-OprM) forming an efflux pump, which rejects incoming toxic molecules into the extracellular environment (1). A low outer membrane permeability combined with a high capacity to efflux toxic compounds provides an intrinsic mechanism for drug resistance. An alternative resistance strategy is not to let the drug get inside the cell. The OMP OprD is involved in the transport of basic amino acids, but also of antibiotics of the carbapenem family (6). Several studies reported that clinical P. aeruginosa strains isolated from patients under carbapenem treatment display an oprD mutation. In their study, Skurnik et al. stumbled on OprD but in an unexpected manner (4). By using a P. aeruginosa transposon (Tn) mutant library, 94% oprD 42% oprD 38% pil Cecum Spleen