**1. Introduction**

We are currently facing an international crisis with many troublesome aspects: new antibiotics are no longer being detected, resistance mechanisms are developing in almost all clinical isolates of bacteria, and the effective treatment of infections is hampered by recurrent infections caused by persistent bacteria. Antibiotic failure is one of the most worrying health issues worldwide [1]. Although resistance acquisition is a natural phenomenon, it is accelerated by antibiotic misuse, inadequate inspection and poorly regulated management of antibiotics have resulted in the appearance and spread of multidrug-resistant (MDR) bacteria abroad in clinical medicine and in the livestock industry [2, 3].

Empirical antibiotic treatment requires monotherapy and combination therapy for suspected cases of *P. aeruginosa* and reduces mortality in patients with serious *P. aeruginosa* infections [4, 5]. However, because of the ability of this bacterium to avoid many of the currently available antibiotics, treatment of *P. aeruginosa* infections has become a great challenge [6]. Recently, the World Health Organization (WHO) has identified carbapenem-resistant *P. aeruginosa* as one of three bacterial species with an urgent need for new antibiotics to be developed to treat infections [7]. In addition, inappropriate treatment use of antibiotics accelerates the production of multidrug-resistant strains of *P. aeruginosa*, resulting in the ineffectiveness

of empirical antibiotic therapy against this microorganism [8]. Resistance to a range of antibiotics, including aminoglycosides, quinolones and β-lactams, is demonstrated by *P. aeruginosa* [9]. Generally, the main mechanisms of *P. aeruginosa* used to fight antibiotic attack can be divided into intrinsic, acquired and adaptive resistance. Low external membrane permeability, the expression of efflux pumps that remove antibiotics from the cell, and the development of antibiotic inactivating enzymes are part of the intrinsic resistance of *P. aeruginosa*. Either horizontal transfer of resistance genes or mutational modifications will achieve the acquired resistance of *P. aeruginosa* [10]. *P. aeruginosa 's* adaptive resistance requires the development of biofilm in the lungs of infected patients, where the biofilm functions as a diffusion barrier to inhibit the access of antibiotics to bacterial cells [11].

The effectiveness and safety of murepavadin in the treatment of infections of the lower respiratory tract caused by *P. aeruginosa* (suspected or confirmed) in patients with ventilation-associated pneumonia or CF-unrelated bronchiectasis (Clinical Trials. gov identifiers NCT02096315 and NCT02096328) have been tested in two clinical trials. However, by July 17, 2019, the trials were stopped because in research participants who had obtained murepavadin, an unusually high level of renal failure had been found. This decision would not impact the production of an aerosolized formulation of murepavadin for topical use [12]. Murepavadin is a particular weapon against *P. aeruginosa*, which separates it from the broad pipeline of antimicrobial natural and synthetic peptides acting against multiple taxa, *P. aeruginosa* included. Recently, several novel peptides with broad antimicrobial activity have been identified, such as antimicrobial peptide DGL13K, Mel4 and melamine (Melimine and Mel4 are chimeric cationic peptides with broad-spectrum antimicrobial activity), Cecropin B, Lysine-based peptidomimetics (LBP-2), Truncated pseudin-2 analogs (Pse-T2), antimicrobial peptide, termed 6 K-F17 (sequence: KKKKKK-AAFAAWAAFAA-NH2), Melittin-derived peptides (MDP1, MDP2) [13–20]. In addition, multidrug-tolerant persistent cells can form in the biofilm that are capable of surviving antibiotic attack; in cystic fibrosis (CF) patients, these cells are responsible for prolonged and recurrent infections [21]. For patients whose infections are resistant to traditional antibiotics, the development of new antibiotics or alternative therapeutic methods for treating *P. aeruginosa* infections is urgently needed. In recent years, new antibiotics with novel modes of action have been investigated, as have new routes of administration and resistance to bacterial enzyme alteration. Compared to traditional antibiotics, some of these newer antibiotics demonstrate excellent in vitro antibacterial activity against *P. aeruginosa* as well as lower minimum inhibitory concentration (MIC) [22, 23]. Moreover, several novel non-antibiotic therapeutic approaches that are highly successful in destroying antibiotic resistant *P. aeruginosa* strains have been documented in recent studies [24]. These approaches include: antimicrobial peptides, phage therapy, inhibition of quorum sensing, iron chelation, the use of nanoparticles, probiotic and vaccine strategy. In order to combat *P. aeruginosa* infections, these therapeutic approaches may be used either as an alternative to or in conjunction with traditional antibiotic therapies.
