Attenuated mutants of Salmonella enterica Typhimurium mediate melanoma regression via an immune response.

The lack of effective treatment options for an increasing number of cancer cases highlights the need for new anticancer therapeutic strategies. Immunotherapy mediated by Salmonella enterica Typhimurium is a promising anticancer treatment. Candidate strains for anticancer therapy must be attenuated while retaining their antitumor activity. Here, we investigated the attenuation and antitumor efficacy of two S. enterica Typhimurium mutants, ΔtolRA and ΔihfABpmi, in a murine melanoma model. Results showed high attenuation of ΔtolRA in the Galleria mellonella model, and invasion and survival in tumor cells. However, it showed weak antitumor effects in vitro and in vivo. Contrastingly, lower attenuation of the attenuated ΔihfABpmi strain resulted in regression of tumor mass in all mice, approximately 6 days after the first treatment. The therapeutic response induced by ΔihfABpmi was accompanied with macrophage accumulation of antitumor phenotype (M1) and significant increase in the mRNAs of proinflammatory mediators (TNF-α, IL-6, and iNOS) and an apoptosis inducer (Bax). Our findings indicate that the attenuated ΔihfABpmi exerts its antitumor activity by inducing macrophage infiltration or reprogramming the immunosuppressed tumor microenvironment to an activated state, suggesting that attenuated S. enterica Typhimurium strains based on nucleoid-associated protein genes deletion could be immunotherapeutic against cancer.

Combined effect of SAR-endolysin LysKpV475 with polymyxin B and Salmonella bacteriophage phSE-5.

Endolysins are bacteriophage (or phage)-encoded enzymes that catalyse the peptidoglycan breakdown in the bacterial cell wall. The exogenous action of recombinant phage endolysins against Gram-positive organisms has been extensively studied. However, the outer membrane acts as a physical barrier when considering the use of recombinant endolysins to combat Gram-negative bacteria. This study aimed to evaluate the antimicrobial activity of the SAR-endolysin LysKpV475 against Gram-negative bacteria as single or combined therapies, using an outer membrane permeabilizer (polymyxin B) and a phage, free or immobilized in a pullulan matrix. In the first step, the endolysin LysKpV475 in solution, alone and combined with polymyxin B, was tested in vitro and in vivo against ten Gram-negative bacteria, including highly virulent strains and multidrug-resistant isolates. In the second step, the lyophilized LysKpV475 endolysin was combined with the phage phSE-5 and investigated, free or immobilized in a pullulan matrix, against Salmonella enterica subsp. enterica serovar Typhimurium ATCC 13311. The bacteriostatic action of purified LysKpV475 varied between 8.125 µg ml-1 against Pseudomonas aeruginosa ATCC 27853, 16.25 µg ml-1 against S. enterica Typhimurium ATCC 13311, and 32.50 µg ml-1 against Klebsiella pneumoniae ATCC BAA-2146 and Enterobacter cloacae P2224. LysKpV475 showed bactericidal activity only for P. aeruginosa ATCC 27853 (32.50 µg ml-1) and P. aeruginosa P2307 (65.00 µg ml-1) at the tested concentrations. The effect of the LysKpV475 combined with polymyxin B increased against K. pneumoniae ATCC BAA-2146 [fractional inhibitory concentration index (FICI) 0.34; a value lower than 1.0 indicates an additive/combined effect] and S. enterica Typhimurium ATCC 13311 (FICI 0.93). A synergistic effect against S. enterica Typhimurium was also observed when the lyophilized LysKpV475 at ⅔ MIC was combined with the phage phSE-5 (m.o.i. of 100). The lyophilized LysKpV475 immobilized in a pullulan matrix maintained a significant Salmonella reduction of 2 logs after 6 h of treatment. These results demonstrate the potential of SAR-endolysins, alone or in combination with other treatments, in the free form or immobilized in solid matrices, which paves the way for their application in different areas, such as in biocontrol at the food processing stage, biosanitation of food contact surfaces and biopreservation of processed food in active food packing.

Salmonella enterica and outer membrane vesicles are current and future options for cancer treatment.

Conventional cancer therapies have many limitations. In the last decade, it has been suggested that bacteria-mediated immunotherapy may circumvent the restrictions of traditional treatments. For example, Salmonella enterica is the most promising bacteria for treating cancer due to its intrinsic abilities, such as killing tumor cells, targeting, penetrating, and proliferating into the tumor. S. enterica has been genetically modified to ensure safety and increase its intrinsic antitumor efficacy. This bacterium has been used as a vector for delivering anticancer agents and as a combination therapy with chemotherapy, radiotherapy, or photothermic. Recent studies have reported the antitumor efficacy of outer membrane vesicles (OMVs) derived from S. enterica. OMVs are considered safer than attenuated bacteria and can stimulate the immune system as they comprise most of the immunogens found on the surface of their parent bacteria. Furthermore, OMVs can also be used as nanocarriers for antitumor agents. This review describes the advances in S. enterica as immunotherapy against cancer and the mechanisms by which Salmonella fights cancer. We also highlight the use of OMVs as immunotherapy and nanocarriers of anticancer agents. OMVs derived from S. enterica are innovative and promising strategies requiring further investigation.

Les misérables: a Parallel Between Antimicrobial Resistance and COVID-19 in Underdeveloped and Developing Countries.

Purpose of Review: The COVID-19 pandemic has been responsible for more than 6.3 million deaths worldwide. During the pandemic, the indiscriminate use of antibiotics has increased, contributing to the spread of multidrug-resistant bacteria. In this review, we aim to determine the spread and impact of antibiotic treatments in patients with COVID-19, focusing on underdeveloped and developing countries. Recent Findings: Meta-analysis revealed that bacterial co-infections and secondary infections are relatively rare in COVID-19 patients, corresponding to less than 20% of hospitalized patients. Even so, most of these patients have received antibiotic treatments. Summary: This review discusses how the COVID-19 pandemic could increase the emergence of multidrug-resistant strains to currently available antibiotics. Initially, we discussed the spread and impact of multidrug resistance of ESKAPE pathogens associated with nosocomial infections and analyzed their risk of secondary infections in patients with COVID-19. Then we highlight three factors related to the spread of resistant bacteria during the current pandemic: overprescription of antibiotics followed by self-medication. Finally, we discussed the lack of availability of diagnostic tests to discriminate the etiologic agent of a disease. All these factors lead to inappropriate use of antibiotics and, therefore, to an increase in the prevalence of resistance, which can have devastating consequences shortly. The data compiled in this study underscore the importance of epidemiological surveillance of hospital isolates to provide new strategies for preventing and controlling infections caused by multidrug-resistant bacteria. In addition, the bibliographic research also highlights the need for an improvement in antibiotic prescribing in the health system.