Bacterial resistance to conventional antibiotics has reached alarming levels, threatening to return to the pre-antibiotic era. Therefore, the search for new antimicrobial compounds that overcome the resistance phenomenon has become a priority. Antimicrobial peptides (AMPs) appear as one of the most promising antibiotic medicines. However, in recent years several AMP-resistance mechanisms have been described. Moreover, the AMP-resistance phenomenon has become more complex due to its association with cross-resistance toward AMP effectors of the host innate immune system. In this context, the use of AMPs as a therapeutic option could be potentially hazardous, since bacteria could develop resistance toward our innate immune system. Here, we review the findings of major studies that deal with the AMP cross-resistance phenomenon.

In the present work, we evaluated the neutralizing capacity of the antibodies induced by dengue virus type 1 and 2 envelope domain III recombinant proteins in monkeys against strains of different dengue virus type 1 and 2 genotypes. Here we demonstrated that dengue virus type 1 and 2 recombinant proteins induced high titers of neutralizing antibodies against different genotype strains.An effective humoral immune response is critical for protecting against dengue viruses (DEN) (12)(13)(14) and is the essential goal of recombinant subunit vaccines based on envelope (E) domain III. Domain III is thought to mediate interactions between the virus and cellular receptors involved in virus attachment (6,21). In addition, many of the most potent anti-DEN neutralizing monoclonal antibodies characterized to date recognize this domain (8, 9,24).There is some evidence that the antibody response to a DEN genotype does not necessarily neutralize homogenotypic DEN strains. In fact, sera from patients infected with DEN type 2 (DEN 2) or DEN 3 show variations in the neutralizing antibody responses against strains isolated early and late during the same epidemic (1, 26). Preclinical studies have exposed that the primary immune responses induced after infection of mice and monkeys with DEN 2 strains belonging to both Asian and American genotypes show differences in the responses of neutralizing antibodies against the same and different strains of infection (4, 5). Based on monoclonal antibody data, changes of specific amino acids in domain III result in the loss of binding of neutralizing monoclonal antibodies (11,19,24). A recent study has also demonstrated that monoclonal antibodies show differentiated neutralizing activities depending on the virulence of the strain (7). Based on the previously reported evidence (1, 4, 5, 7, 11,19,24,26), the humoral immune response induced by a vaccine candidate should be evaluated against strains of different genotypes of each serotype.Previously, we have reported that recombinant proteins containing domain III of DEN 1 or DEN 2 E proteins fused to the P64k protein from Neisseria meningitidis (PD10 and PD5, respectively) induce neutralizing antibodies and partial protection in immunized monkeys (3, 10). In the context of P64k, amino acid changes in E domain III included in the fusion protein have been involved in the antigenicity and immunogenicity of the resultant molecules in the mouse model (28). In the present work, we evaluate the neutralizing antibody activity in sera collected from Macaca fascicularis monkeys immunized with such recombinant proteins against strains of different genotypes.Sera from Macaca fascicularis monkeys previously immunized with DEN 1 or DEN 2 recombinant fusion proteins were evaluated by a plaque reduction neutralization test (PRNT) against DEN 1 or DEN 2 strains belonging to different genotypes of the corresponding serotype (Table 1) (17,23). The E domain III used for the PD10 or PD5 genetic construction belongs to strain DEN 1 Jamaica or DEN 2 Jamaica, respective...

Bacterial resistance to conventional antibiotics is currently a real problem all over the world, making novel antimicrobial compounds a real research priority. Some of the most promising compounds found to date are antimicrobial peptides (AMPs). The benefits of these drugs include their broad spectrum of activity that affects several microbial processes, making the emergence of resistance less likely. However, bacterial resistance to AMPs is an evolving phenomenon that compromises the therapeutic potential of these compounds. Therefore, it is mandatory to understand bacterial mechanisms of resistance to AMPs in depth, in order to develop more powerful AMPs that overcome the bacterial resistance response.

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