Recent Advances in Multi-Drug Resistance (MDR) Efflux Pump Inhibitors of Gram-Positive Bacteria S. aureus

Antibiotic resistance is one of the most pressing health issues of our days. It can arise due to a multiplicity of factors, such as target modification, decrease in the drug uptake, changes in the metabolic pathways and activation of efflux pumps. The overexpression of efflux pumps is responsible for the extrusion of drugs, making antibiotic therapy fail, as the quantity of intracellular antibiotic is not enough to provide the desired therapeutic effect. Efflux pumps can be included in five families according to their composition, nature of substrates, energy source, and number of transmembrane spanning regions. The ABC superfamily is mainly found in Gram-positive bacteria, use ATP as an energy source, and only a limited number of ABC pumps confer multidrug resistance (MDR). On the other hand, the MFS family, most present in Gram-positive bacteria, and the RND family, characteristic of Gram-negative bacteria, are most associated with antibiotic resistance. A wide variety of inhibitors have been disclosed for both families, from either natural or synthetic sources, or even drugs that are currently in therapy for other diseases. The other two families are the SMR, which are the smallest drug efflux proteins known, and the MATE family, whose pumps can also resort to the sodium gradient as an energy source. In this review, it is intended to present a comprehensive review of the classes of efflux pump inhibitors from the various sources, highlighting their structure-activity relationships, which can be useful for medicinal chemists in the pursuit of novel efflux pump inhibitors.

Download Full-text

Novel Antibacterial Strategies for Combating Bacterial Multidrug Resistance

Current Pharmaceutical Design ◽

10.2174/1381612825666191022163237 ◽

2020 ◽

Vol 25 (44) ◽

pp. 4717-4724

Author(s):

Xiao-Ling Xu ◽

Xu-Qi Kang ◽

Jing Qi ◽

Fei-Yang Jin ◽

Di Liu ◽

...

Keyword(s):

Drug Resistance ◽

Multidrug Resistance ◽

Combination Therapy ◽

Efflux Pump ◽

Multidrug Resistant ◽

Multi Drug Resistance ◽

Novel Treatments ◽

Global Problems ◽

Efflux Pump Inhibitors ◽

Multidrug Resistant Pathogens

Background: Antibacterial multidrug resistance has emerged as one of the foremost global problems affecting human health. The emergence of resistant infections with the increasing number of multidrug-resistant pathogens has posed a serious problem, which required innovative collaborations across multiple disciplines to address this issue. Methods: In this review, we will explain the mechanisms of bacterial multidrug resistance and discuss different strategies for combating it, including combination therapy, the use of novel natural antibiotics, and the use of nanotechnology in the development of efflux pump inhibitors. Results: While combination therapy will remain the mainstay of bacterial multi-drug resistance treatment, nanotechnology will play critical roles in the development of novel treatments in the coming years. Conclusion: Nanotechnology provides an encouraging platform for the development of clinically relevant and practical strategies to overcome drug resistance in the future.

Download Full-text

Emergence of Multi-Drug Resistance Gram-Positive Bacteria and New Active Antibiotics

Current Medicinal Chemistry - Anti-Infective Agents ◽

10.2174/1568012054368146 ◽

2005 ◽

Vol 4 (3) ◽

pp. 235-257 ◽

Cited By ~ 6

Author(s):

Stefania Stefani

Keyword(s):

Drug Resistance ◽

Multi Drug Resistance ◽

Gram Positive ◽

Gram Positive Bacteria

Download Full-text

Efflux Pump Inhibitors and Their Role in the Reversal of Drug Resistance

Antibacterial Drug Discovery to Combat MDR ◽

10.1007/978-981-13-9871-1_12 ◽

2019 ◽

pp. 251-275 ◽

Cited By ~ 1

Author(s):

Samreen ◽

Iqbal Ahmad ◽

Faizan Abul Qais ◽

Meenu Maheshwari ◽

Kendra P. Rumbaugh

Keyword(s):

Drug Resistance ◽

Efflux Pump ◽

Efflux Pump Inhibitors

Download Full-text

Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

Microorganisms ◽

10.3390/microorganisms8020191 ◽

2020 ◽

Vol 8 (2) ◽

pp. 191 ◽

Cited By ~ 4

Author(s):

Despoina Koulenti ◽

Elena Xu ◽

Andrew Song ◽

Isaac Yin Sum Mok ◽

Drosos E. Karageorgopoulos ◽

...

Keyword(s):

Safety Profile ◽

Bacterial Infections ◽

Antimicrobial Agents ◽

Treatment Options ◽

Multidrug Resistant ◽

Current Treatment ◽

Multi Drug Resistance ◽

Gram Positive ◽

Treatment Regimens ◽

Gram Positive Bacteria

Antimicrobial agents are currently the mainstay of treatment for bacterial infections worldwide. However, due to the increased use of antimicrobials in both human and animal medicine, pathogens have now evolved to possess high levels of multi-drug resistance, leading to the persistence and spread of difficult-to-treat infections. Several current antibacterial agents active against Gram-positive bacteria will be rendered useless in the face of increasing resistance rates. There are several emerging antibiotics under development, some of which have been shown to be more effective with an improved safety profile than current treatment regimens against Gram-positive bacteria. We will extensively discuss these antibiotics under clinical development (phase I-III clinical trials) to combat Gram-positive bacteria, such as Staphylococcus aureus, Enterococcus faecium and Streptococcus pneumoniae. We will delve into the mechanism of actions, microbiological spectrum, and, where available, the pharmacokinetics, safety profile, and efficacy of these drugs, aiming to provide a comprehensive review to the involved stakeholders.

Download Full-text

Efflux Pump Inhibitors against Nontuberculous Mycobacteria

International Journal of Molecular Sciences ◽

10.3390/ijms21124191 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4191

Author(s):

Laura Rindi

Keyword(s):

Drug Resistance ◽

Efflux Pump ◽

Nontuberculous Mycobacteria ◽

Current Knowledge ◽

New Drugs ◽

Human Pathogens ◽

Intracellular Accumulation ◽

Promising Strategy ◽

Combined Use ◽

Efflux Pump Inhibitors

Over the last years, nontuberculous mycobacteria (NTM) have emerged as important human pathogens. Infections caused by NTM are often difficult to treat due to an intrinsic multidrug resistance for the presence of a lipid-rich outer membrane, thus encouraging an urgent need for the development of new drugs for the treatment of mycobacterial infections. Efflux pumps (EPs) are important elements that are involved in drug resistance by preventing intracellular accumulation of antibiotics. A promising strategy to decrease drug resistance is the inhibition of EP activity by EP inhibitors (EPIs), compounds that are able to increase the intracellular concentration of antimicrobials. Recently, attention has been focused on identifying EPIs in mycobacteria that could be used in combination with drugs. The aim of the present review is to provide an overview of the current knowledge on EPs and EPIs in NTM and also, the effect of potential EPIs as well as their combined use with antimycobacterial drugs in various NTM species are described.

Download Full-text

Impact of an Intervention to Control Imipenem-Resistant Acinetobacter baumannii and Its Resistance Mechanisms: An 8-Year Survey

Frontiers in Microbiology ◽

10.3389/fmicb.2020.610109 ◽

2021 ◽

Vol 11 ◽

Cited By ~ 1

Author(s):

Lida Chen ◽

Pinghai Tan ◽

Jianming Zeng ◽

Xuegao Yu ◽

Yimei Cai ◽

...

Keyword(s):

Drug Resistance ◽

Acinetobacter Baumannii ◽

Bacterial Resistance ◽

Efflux Pump ◽

Resistance Mechanism ◽

Resistance Mechanisms ◽

Multi Drug Resistance ◽

Minimal Inhibitory Concentrations ◽

Resistance Rates ◽

The Impact

BackgroundThis study aimed to examine the impact of an intervention carried out in 2011 to combat multi-drug resistance and outbreaks of imipenem-resistant Acinetobacter baumannii (IRAB), and to explore its resistance mechanism.MethodsA total of 2572 isolates of A. baumannii, including 1673 IRAB isolates, were collected between 2007 and 2014. An intervention was implemented to control A. baumannii resistance and outbreaks. Antimicrobial susceptibility was tested by calculating minimal inhibitory concentrations (MICs), and outbreaks were typed using pulsed-field gel electrophoresis (PFGE). Resistance mechanisms were explored by polymerase chain reaction (PCR) and whole genome sequencing (WGS).ResultsFollowing the intervention in 2011, the resistance rates of A. baumannii to almost all tested antibiotics decreased, from 85.3 to 72.6% for imipenem, 100 to 80.8% for ceftriaxone, and 45.0 to 6.9% for tigecycline. The intervention resulted in a decrease in the number (seven to five), duration (8–3 months), and departments (five to three) affected by outbreaks; no outbreaks occurred in 2011. After the intervention, only blaAMPC (76.47 to 100%) and blaTEM–1 (75.74 to 96.92%) increased (P < 0.0001); whereas blaGES–1 (32.35 to 3.07%), blaPER–1 (21.32 to 1.54%), blaOXA–58 (60.29 to 1.54%), carO (37.50 to 7.69%), and adeB (9.56 to 3.08%) decreased (P < 0.0001). Interestingly, the frequency of class B β-lactamase genes decreased from 91.18% (blaSPM–1) and 61.03% (blaIMP–1) to 0%, while that of class D blaOXA–23 increased to 96.92% (P < 0.0001). WGS showed that the major PFGE types causing outbreaks each year (type 01, 11, 18, 23, 26, and 31) carried the same resistance genes (blaKPC–1, blaADC–25, blaOXA–66, and adeABC), AdeR-S mutations (G186V and A136V), and a partially blocked porin channel CarO. Meanwhile, plasmids harboring blaOXA–23 were found after the intervention.ConclusionThe intervention was highly effective in reducing multi-drug resistance of A. baumannii and IRAB outbreaks in the long term. The resistance mechanisms of IRAB may involve genes encoding β-lactamases, efflux pump overexpression, outer membrane porin blockade, and plasmids; in particular, clonal spread of blaOXA–23 was the major cause of outbreaks. Similar interventions may also help reduce bacterial resistance rates and outbreaks in other hospitals.

Download Full-text

Incidence and Bacterial Etiologies of Surgical Site Infections in a Public Hospital, Addis Ababa, Ethiopia

The Open Microbiology Journal ◽

10.2174/1874285801913010301 ◽

2019 ◽

Vol 13 (1) ◽

pp. 301-307

Author(s):

Alem A. Kalayu ◽

Ketema Diriba ◽

Chuchu Girma ◽

Eman Abdella

Keyword(s):

Drug Resistance ◽

Addis Ababa ◽

Surgical Site Infections ◽

Resistant Bacteria ◽

Coagulase Negative Staphylococci ◽

Gram Positive ◽

Cross Sectional ◽

Gram Negative ◽

Clinical Criteria ◽

Gram Positive Bacteria

Background: Surgical Site Infections (SSIs) are among the frequently reported healthcare-acquired infections worldwide. Successful treatment of SSIs is affected by the continuous evolvement of drug-resistant microbes. This study investigated the incidence of SSIs, identifying the major etiologic agents and their drug resistance patterns in Yekatit 12 Hospital, Ethiopia. Methods: A cross-sectional study was conducted on 649 patients who underwent surgery at Yekatit 12 hospital from April 2016 to April 2017. Socio-demographic and clinical data were collected from each patient on admission. After surgery, they were followed for SSI occurrence. SSI was initially diagnosed by a senior surgeon based on standard clinical criteria and then confirmed by culture. Isolates were tested for drug resistance according to the clinical and laboratory standards institute guideline. Results: Of the 649 study participants, 56% were females. Their age ranged from 9 months to 88 years with a median age of 37 years. The incidence of culture-confirmed SSI was 10.2% (66/649) where 73 isolates were recovered. About two-third of the isolates were Gram-positive bacteria. Staphylococcus aureus was the most frequently isolated (27/73, 37%) followed by Coagulase-negative staphylococci (18/73, 24.7%), Escherichia coli (11/73, 15.1%) and Klebsiella species (10/73, 13.7%). About 89% and 44% of S. aureus isolates were resistant to penicillin and trimethoprim-sulfamethoxazole, respectively. MRSA constituted 11% of the S. aureus isolates. All the Gram-negative isolates were resistant to ampicillin and trimethoprim-sulfamethoxazole but susceptible to amikacin and meropenem. Klebsiella species showed 70-100% resistance to ceftazidime, cefuroxime, augmentin, chloramphenicol, ciprofloxacin, cefepime and gentamicin. About 82% of E. coli isolates were resistant for chloramphenicol, cefepime, ceftazidime, augmentin, cefuroxime and 64% for gentamicin and ciprofloxacin. Conclusion: The incidence of surgical site infection in Yekatit 12 hospital is 10.2%. Most of the SSIs were due to Gram-positive bacteria. Gram-negative isolates showed high resistance to the most commonly prescribed drugs. No resistance was found for meropenem indicating the absence of carbapenem-resistant bacteria. SSI treatments should be guided by culture and drug resistance test. Better infection prevention practices and continuous surveillance of antimicrobial resistance in the hospital are recommended for better patient care.

Download Full-text

High resolution melting analysis and detection of Leishmania resistance: the role of multi drug resistance 1 gene

Genes and Environment ◽

10.1186/s41021-021-00210-5 ◽

2021 ◽

Vol 43 (1) ◽

Author(s):

Maryam Fekri Soofi Abadi ◽

Alireza Moradabadi ◽

Reza Vahidi ◽

Saeedeh Shojaeepour ◽

Sara Rostami ◽

...

Keyword(s):

Drug Resistance ◽

High Resolution ◽

High Resolution Melting ◽

Efflux Pump ◽

Mdr1 Gene ◽

Multi Drug Resistance ◽

Sequencing Method ◽

Melting Analysis ◽

Resistance Protein

Abstract Background Pentavalent antimonial compounds are currently used to treat leishmaniasis and resistance to these drugs is a serious problem. Multidrug resistance protein is an efflux pump of the cell membrane that expels foreign compounds. This study designed to evaluate the mutations in the multi-drug resistance 1 (MDR1) gene, in biopsy specimens of Leishmania tropica, with high resolution melting (HRM) method. In this experimental study, genomic DNA was extracted from 130 patients with skin leishmaniasis. Then, nucleotide changes were investigated throughout the gene using HRM and sequencing methods. The samples categorized in 5 groups by differences in the melting temperature (Tm). Result The nucleotide changes analysis showed that 61% of the samples of different groups that were unresponsive to drug had mutations in the MDR1 gene, which were also confirmed by the sequencing method. These mutations can be one of the factors responsible for non-responsiveness to the treatment. Conclusion According to the findings, it seems that mutation in MDR1 gene could be responsible for drug resistance to pentavalent antimonial compounds. Furthermore, HRM method can be used to diagnose drug resistance in leishmaniasis. It is also recommended that further studies be done regarding the importance of drug resistance in the leishmania affected patients.

Download Full-text