Squalamine displays remarkable efficacy against Gram-negative and Gram-positive bacteria. An analysis of squalamine’s antibacterial efficiency at 250 mg/L was studied against the reference bacterial strains Escherichia coli (E. coli) (American Type Culture Collection (ATCC) 25922), Pseudomonas aeruginosa (P. aeruginosa) (ATCC 27853), Staphylococcus aureus (S. aureus) (ATCC 25923), and a clinical isolate Streptococcus pneumoniae (S. pneumoniae) (recovered from the sputum of a cystic fibrosis patient), and compared to colistin [9]. Squalamine exhibited complete killing of P. aeruginosa and E. coli reference strains in 2 h by disrupting membranes, whereas colistin required 4 h. Both compounds react by creating active lesions in the bacterial membrane, leading to emptied bacterial cells. Remarkably, squalamine showed a direct bactericidal effect against the S. aureus reference strain, resulting in a dramatic disruption of the bacterial membrane, with drained cytoplasmic content. Then, the effects of squalamine on bacterial membrane integrity were investigated by measuring intracellular Adenosine triphosphate (ATP) release kinetics for 20 min. It was described that squalamine induced a rapid ATP release from S. aureus and S. pneumoniae that reached 100% of maximal efflux, and depolarization of bacterial membranes was observed [9]. These results indicate that squalamine acts by disrupting the outer membranes of Gram-negative bacteria by a detergent-like mechanism of action and by depolarizing the bacterial membranes of Gram-positive bacteria (Figure 1) [9]. These squalamine mechanisms of action are preserved even in MDR clinical isolates. MDR bacteria have an ability to overexpress different mechanisms of action of resistance. It that includes drug efflux pumps production, membrane permeability alteration, and enzymatic barrier activation. All these mechanisms of action are well-known to induce a high level of resistance towards quinolones, ß-lactams, and phenicols [13,17,18].

The antibacterial activity of squalamine and synthesized aminosterol derivatives (ASD 1 [7-(1,4-diaminobutane)-cholest-5-ene-3β-ol] and ASD 2 [7β-(1,4-diaminobutane)-cholestan-3β-ol) (Table 1) was investigated for the first time against a large range of MDR bacteria involved in clinical pathologies like cystic fibrosis (CF). Interestingly, antibacterial experimentations revealed minimal inhibitory concentrations (MICs) for E. coli (ATCC 25922) of 2 mg/L for squalamine and 4 mg/L for both ASD 1 and ASD 2. MICs were 8 mg/L for squalamine, 4 mg/L and 8 mg/L for ASD 1 and ASD 2, respectively, for P. aeruginosa (ATCC 27853) strain. MICs were 2 mg/L for squalamine, 2 mg/L and 4 mg/L for ASD 1 and ASD 2, respectively, for S. aureus (ATCC 25923) strain. ASDs were also active against S. pneumoniae isolates with a MIC of 32 mg/L, and against others Gram-positive isolates, with MICs ranging from 0.5 to 8 mg/L. Some studies have suggested that there is a similarity of certain mechanisms of action of ASDs and polymyxins, which suggests that the antibacterial activity of ASDs against Gram-positive bacteria is reduced (Figure 1) [19].

The studies of the antimicrobial effects of squalamine have been extended from the experimental phase to the preclinical and clinical phase. Squalamine has been tested as a therapeutic agent to fight against the colonization of the skin by S. aureus. Cutaneous colonization was studied in a mouse model infected by methicillin-susceptible S. aureus (ATCC 25923) and methicillin-resistant S. aureus (MRSA) (Collection de Souches de l’Unité des Rickettsies (CSUR) P102) at 10⁶–10⁸ colony-forming unit/mL (cfu/mL), separately. Squalamine revealed a high degree of viable S. aureus load reduction with bactericidal effect up to 4-log₁₀, during a 2-day experiment. A single dose of squalamine formulated at 1% in a petrolatum-based cream completely eradicated S. aureus (Table 1) [24].

Antidermatophyte effect of squalamine and of a synthetic aminosterol derivative was also investigated and showed significant in vitro activity against Trichophyton rubrum (T. rubrum), Trichophyton mentagrophytes (T. mentagrophyte), Trichophyton soudanense (T. soudanense), Microsporum canis (M. canis), Microsporum audouinii (M. audouinii), Microsporum persicolor (M. persicolor), Microsporum cookie (M. cookie), and Microsporum gypseum (M. gypseum), with MICs ranging from 4–16 mg/L for squalamine, and from 2–8 mg/L for the synthetic aminosterol derivative (Table 1) (Figure 2) [25]. These findings supported further clinical studies of aminosterols activity against dermatophyte infections, introduced by a double-blinded randomized placebo-controlled clinical trial focused on squalamine effect on tinea capitis. This pathology represents a common fungal infection of the scalp, hair follicles, and hair shafts [57]. Clinical trial phase II study shows a statistically significant higher hairgrowth score within the tinea capitis lesions treated with 1% squalamine ointment. In addition, squalamine showed a favorable safety profile when administered topically, as no clinical or biological adverse events were recorded in treated patients. In this clinical trial, squalamine ointment application was well tolerated and showed an encouraging partial clinical activity for the treatment of tinea (Table 1) [58].

3.2. Antiangiogenesis and Antitumor Activity of Squalamine and Its Derivatives

3.3. Potential Effects of Squalamine on Neurodegenerative Diseases and Other Pathologies

3.3.1. Parkinson’s Disease