Peptides with Therapeutic Potential against *Acinetobacter baumanii* Infections

*Karyne Rangel and Salvatore Giovanni De-Simone*

#### **Abstract**

Antibiotic poly-resistance (multi drug-, extreme-, and pan-drug resistance) is a major global threat to public health. Unfortunately, in 2017, the World Health Organization (WHO) introduced the carbapenemresistant isolates in the priority pathogens list for which new effective antibiotics or new ways of treating the infections caused by them are urgently needed. *Acinetobacter baumannii* is one of the most critical ESKAPE pathogens for which the treatment of resistant isolates have caused severe problems; its clinically significant features include resistance to UV light, drying, disinfectants, and antibiotics. Among the various suggested options, one of the antimicrobial agents with high potential to produce new anti-Acinetobacter drugs is the antimicrobial peptides (AMPs). AMPs are naturally produced by living organisms and protect the host against pathogens as a part of innate immunity. The main mechanisms action of AMPs are the ability to cause cell membrane and cell wall damage, the inhibition of protein synthesis, nucleic acids, and the induction of apoptosis and necrosis. AMPs would be likely among the main anti-*A. baumannii* drugs in the post-antibiotic era. Also, the application of computer science to increase anti-*A. baumannii* activity and reduce toxicity is also being developed.

**Keywords:** RAMP, *Acinetobacter baumannii*, resistance, action mechanism

### **1. Introduction**

Microbial infections contribute substantially to global mortality trends. Antibiotic resistance is one of the biggest challenges for the clinical sector, industry, environment, and societal development. Unfortunately, the emergence of drug-resistant pathogens is rapidly growing, and the world is heading toward the post-antibiotic era [1, 2]. Bacteria possess three defined types of antimicrobial resistance: intrinsic, acquired, and phenotypic or adaptive resistance [3–11]. Although there are multiple causes of the resistance phenomenon, it is considered that antimicrobial resistance is an old natural phenomenon when microbes are exposed to antimicrobial drugs, with an accelerated evolution triggered not only by the abusive use of antibiotics but also such as wrong choices, inadequate dosing, and poor adherence to treatment guidelines that contribute to the increasing antimicrobial resistance selection [12, 13]. In addition, antibiotic treatment for difficult-totreat multidrug-resistant bacterial infections is limited [13]. ESKAPE pathogens

(*Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, A. baumannii, Pseudomonas aeruginosa*, *Enterobacter* species) are among the most common opportunistic pathogens in nosocomial infections [14]. The abbreviation ESKAPE reflects the ability of these organisms to "escape" killing by antibiotics and defy eradication by conventional therapies, which accounts for increased morbidity and mortality for improved resource utilization in healthcare [15]. One of the ESKCAPE pathogens responsible for nosocomial and community-acquired infections is *A. baumannii*, a Gram-negative, non-motile, non-fermentative, and non-sporulated bacterium Moraxellaceae family [16] that is part of the *Acinetobacter calcoaceticus*– *A. baumannii* complex (Acb). Currently, six species, namely *A. calcoaceticus*, *A. baumannii*, *A. pittii*, *A. nosocomialis*, *A. seifertii*, and *A. lactucae* (a later heterotypic synonym of *A. dijkshoorniae*) [17, 18], belonging to the Acb complex have been associated with human diseases [19]. Even though these species differ in antimicrobial resistance, pathogenicity, and epidemiology [20], the Acb complex is genetically and physiologically highly related, making it difficult to distinguish them phenotypically with standard laboratory methods [21]. Of all the species in the Acb complex, *A. baumannii* is the most widespread in hospitals, even associated with an increased risk of morbidity, mortality, high treatment costs, and long periods of hospitalization [22]. *A. baumannii* causes various infections, including wounds, skin, urinary tract infections, pneumonia, meningitis, and bacteremia [23, 24]. There are several nomenclatures in the literature based on the number of resistance classes of antibiotics. According to Magiorakos et al. (2012), a multidrugresistant (MDR) strain is resistant to at least one antimicrobial in more than three classes of antimicrobials; and extensively drug-resistant (XDR) strain is one resistant to at least one antimicrobial in all classes of antimicrobials except two or fewer types, and a pan drug-resistant (PDR) strain is resistant to all antimicrobial agents [25]. *A. baumannii* has globally emerged as a highly troublesome nosocomial pathogen revealing MDR, XDR, and PDR phenotypes, and unfortunately, evidence has shown an increased *A. baumannii* antibiotic resistance over time [26]. *A. baumannii* is one of the most critical and fearful pathogens with treatment options limited due to many aspects: its extended virolome and resistome, evasion of the host's immune effectors, ability to survive in extreme environmental conditions, to grow in biofilms, and to switch to latent growth forms with a minimal metabolic rate [27, 28]. The World Health Organization (WHO) has recently published a report, which also highlighted *A. baumannii* resistant to carbapenems (CRAb) [29, 30] which was classified in the group of "priority 1 for research and develop new antibiotic treatments" and was considered as a "critical" pathogen [31]. One of the antimicrobial agents with high potential for research and development of anti-*Acinetobacter* drugs is the antimicrobial peptides [32]. This chapter aimed to review the powerful antimicrobial peptides described with activity against *A. baumannii* multiresistant*.*
