Non-Lytic Antibacterial Peptides That Translocate Through Bacterial Membranes to Act on Intracellular Targets

Abstract

The advent of multidrug resistance among pathogenic bacteria has attracted great attention worldwide. As a response to this growing challenge, diverse studies have focused on the development of novel anti-infective therapies, including antimicrobial peptides (AMPs). The biological properties of this class of antimicrobials have been thoroughly investigated, and membranolytic activities are the most reported mechanisms by which AMPs kill bacteria. Nevertheless, an increasing number of works have pointed to a different direction, in which AMPs are seen to be capable of displaying non-lytic modes of action by internalizing bacterial cells. In this context, this review focused on the description of the in vitro and in vivo antibacterial and antibiofilm activities of non-lytic AMPs, including indolicidin, buforin II PR-39, bactenecins, apidaecin, and drosocin, also shedding light on how AMPs interact with and further translocate through bacterial membranes to act on intracellular targets, including DNA, RNA, cell wall and protein synthesis.

Inoculum effect of antimicrobial peptides

“…It is also worth mentioning that, in addition to their antimicrobial action, some of these peptides (e.g., LL-37) exert other activities, including immunomodulation and endotoxin neutralisation [Xhindoli 2016]. Other AMPs enter the cell through transporters, without significantly perturbing its membranes, and act on specific intracellular proteins [Cardoso 2019]. As examples of such peptides we included the proline-rich drosocin (in non-glycosylated from) [Bulet 1993, Otvos 2000 as well as fragments 1-16 and 1-17 of bactenecin 7 [Sadler 2002, Podda 2006, Mardirossian 2014, Seefeldt 2016.…”

Adaptive and Mutational Responses to Peptide Dendrimer Antimicrobials in Pseudomonas aeruginosa

“…Subsequent insertion of the polymyxins into the lipid layer causes phospholipid perturbations in both membranes, leading to osmotic imbalance and cell death. Nonlytic AMPs may also have intracellular targets and can block cell division by different mechanisms (8,9). The most widely used AMP in the clinical setting is colistin (polymyxin E), which has gained renewed interest because it is efficacious against multidrug-resistant (MDR) Gram-negative bacteria (10-12).…”

Antimicrobial peptides as therapeutic agents: opportunities and challenges

“…Furthermore, AMPs can cause membrane permeabilization by forming a complex with small organic anions carrying them across the membrane [10,31] or by inducing molecular electroporation, where the charged AMPs generate a transmembrane potential resulting in pore formation and molecule translocation [32,33]. Additionally, AMPs can induce the formation of non-bilayer intermediates internalizing the peptide within the membrane, followed by collapse of the intermediate and peptide release [30,34], whereas according to the non-lytic membrane depolarization model, the AMPs primarily cause dissipation of the membrane potential without significant structural damage of the membrane [10,35]. Interestingly, several AMPs have been described to alter the lipid phase behavior in the bacterial membrane through direct interactions with lipids that compose the membranes including inducing positive membrane curvature, negative membrane curvature, and cubic lipid phases [30,34].…”

“…Membrane permeabilization is also a key step allowing certain AMPs to translocate into the bacterial cytoplasm to target intracellular processes such as the synthesis of DNA, RNA, and protein, enzymatic activity, cell wall synthesis, and protein folding [10,37,38,40]. Examples of AMPs with intracellular targets include teixobactin that prevents cell wall synthesis by binding the peptidoglycan precursor lipid II [41], indolicidin that binds to DNA thereby inhibiting DNA replication [35], the larvae peptide Lser-PRP2 that is suggested to inhibit protein folding by binding to the bacterial chaperone DnaK [42], and the proline-rich peptide Bac5 that blocks translation by binding to ribosomes [43].…”