## 6 AMPs--Goods vs. Bads, and the Long Way towards Clinical Application
Polymycin and colistin, which are cationic peptides in use for decades, have regained interest lately, due to their strong activity against multi-drug resistant Gram-negative pathogens. Their ability to bind the lipid A component of LPS makes them precious, the last resource weapons to fight septic shock, notwithstanding their known nephrotoxicity. Resistance has emerged, however, and is spreading at an alarming pace, putting the effectiveness of these valuable therapeutics at risk [170; 171]. Last but not least, daptomycin. This membrane-active cyclic lipopeptide has received the green light from the FDA in 2003 to treat Gram-positive infections. It is believed that its mechanism of action differs from that of other AMPs since daptomycin causes bacterial membrane depolarization rather than membrane disruption and pore formation [172]. In recent years, resistance in _Staphylococcus aureus_ has been more and more frequently reported, and the search for substitutes that might prolong the clinical use of this important antibiotic is actively underway [173]. The concern caused by AMPs resistance is clearly transmitted by a very recent clinical trial aimed at evaluating the efficacy of oral colistin-neomycin in preventing multidrug-resistant _Enterobacterales_ (MDR-E) infections in solid organ transplant recipients. In the trial's frame, a 14-day regimen of oral colistin and neomycin did not reduce MDR-E infections, and four liver-recipients developed colistin resistance [174]. A study of the molecular mechanisms of colistin resistance in environmental isolates of _Acinetobacter baumannii_, recovered from hospital wastewater and wastewater treatment plant, has shown that all isolates had increased levels of eptA mRNA and decreased levels of lpxA and lpxD mRNA; the eptA gene, in particular, could indicate its main role in colistin resistance through lipid A modification [175]. Authors hypothesized that when untreated hospital wastewater is released into the urban sewage, it might contain colistin-susceptible _A. baumannii_, and that resistance might emerge in wastewater itself following exposure to pollutants, such as cationic surfactants, and subsequently spread in the environment [175]. Looking at the bright side, things can always improve. Recent work has shown that kynomycin, a new daptomycin analog, was endowed with enhanced activity against both methicillin-resistant _S. aureus_ and vancomycin-resistant _Enterococcus_, with improved pharmacokinetics and lower cytotoxicity than daptomycin [176]. Freshly acquired data suggest that physico-chemical features like Ca\({}^{2+}\) binding and Ca\({}^{2+}\)-mediated oligomerization could explain kynomycin's enhanced antibacterial activity [177]. Even a hasty glance at the AMPs pipeline conveys the level of difficulty at bringing these molecules to the market, either for topical or systemic treatment [166; 178]. After many failures, however, a couple of promising candidates loom on the horizon, at least for some therapeutic indications. Polyphor is developing the synthetic lipopeptide murepavadin, a member of a novel class of antibiotics that combine high-affinity binding to both LPS and outer membrane proteins, resulting in high specificity towards Gram-negative bacteria and effective bactericidal activity. Murepavadin, in particular, targets the lipopolysaccharidetransport protein D (LptD), an outer membrane protein on _Pseudomonas aeruginosa_, leading to cell death. Phase 3 clinical trials investigating the safety and efficacy of intravenous murepavadin have been prematurely stopped due to a rise of creatinine concentration in the serum of patients treated with the AMP, indicating renal failures [179; 180]. Despite these disappointing results, Polyphor plans to continue the development of inhaled murepavadin to treat chronic _P. aeruginosa_ infections associated with cystic fibrosis.