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Bioactive Antimicrobial Peptides as Therapeutic Agents for Infected Diabetic Foot Ulcers.

ABSTRACT: Diabetic foot ulcer (DFU) is a devastating complication, affecting around 15% of diabetic patients and representing a leading cause of non-traumatic amputations. Notably, the risk of mixed bacterial-fungal infection is elevated and highly associated with wound necrosis and poor clinical outcomes. However, it is often underestimated in the literature. Therefore, polymicrobial infection control must be considered for effective management of DFU. It is noteworthy that antimicrobial resistance is constantly rising overtime, therefore increasing the need for new alternatives to antibiotics and antifungals. Antimicrobial peptides (AMPs) are endogenous peptides that are naturally abundant in several organisms, such as bacteria, amphibians and mammals, particularly in the skin. These molecules have shown broad-spectrum antimicrobial activity and some of them even have wound-healing activity, establishing themselves as ideal candidates for treating multi-kingdom infected wounds. Furthermore, the role of AMPs with antifungal activity in wound management is poorly described and deserves further investigation in association with antibacterial agents, such as antibiotics and AMPs with antibacterial activity, or alternatively the application of broad-spectrum antimicrobial agents that target both aerobic and anaerobic bacteria, as well as fungi. Accordingly, the aim of this review is to unravel the molecular mechanisms by which AMPs achieve their dual antimicrobial and wound-healing properties, and to discuss how these are currently being applied as promising therapies against polymicrobial-infected chronic wounds such as DFUs.

SUBMITTER: Da Silva J

PROVIDER: S-EPMC8699205 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCosts related to diabetic foot ulcer (DFU) care are greater than $1 billion annually and rising. We sought to describe the impact of diabetes mellitus (DM) on foot ulcer admissions in the United States, and to investigate potential explanations for rising hospital costs.MethodsThe Nationwide Inpatient Sample (2005-2010) was queried using International Classification of Diseases, 9th Revision (ICD-9) codes for a primary diagnosis of foot ulceration. Multivariable analyses were used to compare outcomes and per-admission costs among patients with foot ulceration and DM versus non-DM.ResultsIn total, 962,496 foot ulcer patients were admitted over the study period. The overall rate of admissions was relatively stable over time, but the ratio of DM versus non-DM admissions increased significantly (2005: 10.2 vs. 2010: 12.7; P < 0.001). Neuropathy and infection accounted for 90% of DFU admissions, while peripheral vascular disease accounted for most non-DM admissions. Admissions related to infection rose significantly among DM patients (2005: 39,682 vs. 2010: 51,660; P < 0.001), but remained stable among non-DM patients. Overall, DM accounted for 83% and 96% of all major and minor amputations related to foot ulcers, respectively, and significantly increased cost of care (DM: $1.38 vs. non-DM: $0.13 billion/year; P < 0.001). Hospital costs per DFU admission were significantly higher for patients with infection compared with all other causes ($11,290 vs. $8,145; P < 0.001).ConclusionsDiabetes increases the incidence of foot ulcer admissions by 11-fold, accounting for more than 80% of all amputations and increasing hospital costs more than 10-fold over the 5 years. The majority of these costs are related to the treatment of infected foot ulcers. Education initiatives and early prevention strategies through outpatient multidisciplinary care targeted at high-risk populations are essential to preventing further increases in what is already a substantial economic burden.

Project description:BackgroundThe study aimed at (i) characterizing the mode of transmission of bla(CTX-M) and bla(TEM-1) among extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli strains isolated from infected diabetic foot ulcers, and (ii) identifying the risk factors for "sex-associated multidrug resistant Gram-negative bacterial (MDRGNB)-infection status" of the ulcers.MethodsSeventy-seven diabetic patients having clinically infected foot ulcers were studied in a consecutive series. The E. coli strains isolated from the ulcers were screened for bla(CTX-M), bla(TEM-1), armA, rmtA and rmtB during the 2-year study-period. PCR amplified bla(CTX-M) genes were cloned and sequenced. Enterobacterial repetitive intergenic consensus (ERIC)-PCR was used for the analysis of genetic relatedness of the ESBL-producers. Risk factors for "sex-associated MDRGNB-infection status" of ulcers were assessed. Modeling was performed using Swiss-Model-Server and verified by Procheck and verify3D programmes. Discovery Studio2.0 (Accelrys) was used to prepare Ramachandran plots. Z-scores were calculated using 'WHAT IF'-package. Docking of cefotaxime with modeled CTX-M-15 enzyme was performed using Hex5.1.ResultsAmong 51 E. coli isolates, 14 (27.5%) ESBL-producers were identified. Only 7 Class1 integrons, 2 bla(CTX-M-15), and 1 bla(TEM-1) were detected. Ceftazidime and cefotaxime resistance markers were present on the plasmidic DNA of both the bla(CTX-M-15) positive strains and were transmissible through conjugation. The residues Asn132, Glu166, Pro167, Val172, Lys234 and Thr235 of CTX-M-15 were found to make important contacts with cefotaxime in the docked-complex. Multivariate analysis proved 'Glycemic control at discharge' as the single independent risk factor.ConclusionsMale diabetic patients with MDRGNB-infected foot ulcers have poor glycemic control and hence they might have higher mortality rates compared to their female counterparts. Plasmid-mediated conjugal transfer, albeit at a low frequency might be the possible mechanism of transfer of bla(CTX-M-15) resistance marker in the present setting. Since the docking results proved that the amino acid residues Asn132, Glu166, Pro167, Val172, Lys234 and Thr235 of CTX-M-15 (enzyme) make important contacts with cefotaxime (drug) in the 'enzyme-drug complex', researchers are expected to duly utilize this information for designing more potent and versatile CTX-M-inhibitors.

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Bioactive Antimicrobial Peptides as Therapeutic Agents for Infected Diabetic Foot Ulcers.

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