Multiple Drug-resistant Strains Research Articles

Insights into the Inhibition of Aeromonas hydrophila d-Alanine-d-Alanine Ligase by Integration of Kinetics and Structural Analysis.

Aeromonas hydrophila, a pathogenic bacterium, is harmful to humans, domestic animals, and fishes and, moreover, of public health concern due to the emergence of multiple drug-resistant strains. The cell wall has been discovered as a novel and efficient drug target against bacteria, and d-alanine-d-alanine ligase (Ddl) is considered as an essential enzyme in bacterial cell wall biosynthesis. Herein, we studied the A. hydrophila HBNUAh01 Ddl (AhDdl) enzyme activity and kinetics and determined the crystal structure of AhDdl/d-Ala complex at 2.7 Å resolution. An enzymatic assay showed that AhDdl exhibited higher affinity to ATP (Km: 54.1 ± 9.1 μM) compared to d-alanine (Km: 1.01 ± 0.19 mM). The kinetic studies indicated a competitive inhibition of AhDdl by d-cycloserine (DCS), with an inhibition constant (Ki) of 120 μM and the 50% inhibitory concentrations (IC50) value of 0.5 mM. Meanwhile, structural analysis indicated that the AhDdl/d-Ala complex structure adopted a semi-closed conformation form, and the active site was extremely conserved. Noteworthy is that the substrate d-Ala occupied the second d-Ala position, not the first d-Ala position. These results provided more insights for understanding the details of the catalytic mechanism and resources for the development of novel drugs against the diseases caused by A. hydrophila.

Chemical reactivity and bioactivity properties of pyrazinamide analogs of acetylsalicylic acid and salicylic acid using conceptual density functional theory

Conventional drugs used to treat Tuberculosis (TB) are becoming ineffective due to the occurrence of multiple drug resistant strains of tuberculosis (TB). This has made the TB disease a a serious global health dilemma. Hence, there is desperate necessity for the advancement of new drugs. In this work, the chemical reactivity and bioactivity of several analogs ofpyrazinamide (PZA) were investigated. PZA is one of the first-line of drugs used to treat tuberculosis and is a key contributor to shortening the treatment time for the disease. Chemical reactivity descriptors of pyrazinamide (PZA) and its analogs of acetylsalicyclic acid and salicyclic acid were investigated using conceptual density functional theory in water as a solvent at the MN12SX/Def2TZVP level of theory. Results have shown that all PZA analogs have improved their global and local reactivity indeces as compared to pyrazinamide based on its electronegativity, electrodonating power, electroaccepting power, eletrophilicity, global hardness and dual descriptor condensed fukui indexes. Moreover, their pKa values are slightly higher than PZA. In terms of its drug-likeness, all PZA analogs passed the Lipinski's Rule of Five criteria. Furthermore, their bioactivity scores are significantly better than pyrazinamide indicating good reaction to G-Protein Coupled Receptor (GPCR) ligands, kinase inhibitors, ion channel modulators, nuclear receptor ligands, protease inhibitors and other enzyme targets. Overall, the PZA analogs are found to be promising anti-tuberculosis drugs. Based on global and local reactivity descriptors, pKa and bioactivity scores, PZA analog of 5-n-Octanoylsalicylic acid is the most reactive among the PZA analogs tested.

High-Level Aminoglycoside Resistance in Enterococcus Faecalis and Enterococcus Faecium; as a Serious Threat in Hospitals.

The present work aimed to evaluate the frequency of aminoglycoside- modifying enzymes encoding genes in the E. faecalis and E. faecium and their antibiotic resistance profile. A total of 305 different clinical samples were subjected for identification and antibiotic susceptibility test. The high-level aminoglycoside resistance was identified by MIC and Kirby Bauer disc diffusion method. The prevalence of aac (6')-Ie-aph (2'')-Ia, aph (3')-IIIa and ant (4')- Ia genes was determined by multiplex- PCR. In total, 100 enterococci strains were isolated. The prevalence of E. faecalis and E. faecium isolates was 78% and 22%, respectively. All isolates were susceptible to linezolid. So, all E. faecalis were susceptible to vancomycin but, 36.4% of E. faecium were resistant to it. The prevalence of multiple drug resistance strains was 100% and 67.9% of E. faecium and E. faecalis, respectively. High-level-gentamicin and streptomycin resistant rates were as follows; 26.9% and 73.1% of E. faecalis and 77.3% and 90.1% of E. faecium. Conclucion: The results of the current study showed a high frequency of aac (6')-Ie-aph (2'')-Ia genes among enterococcal isolates. A high rate of resistance to antimicrobials in Enterococcus is obviously problematic, and a novel policy is needed to decrease resistance in these microorganisms.

Interaction between the Antimalarial Drug Dispiro-Tetraoxanes and Human Serum Albumin: A Combined Study with Spectroscopic Methods and Computational Studies.

Dispiro-tetraoxanes, a class of fully synthetic peroxides which can be used as an antiplasmodial remedy for multiple drug-resistant strains of Plasmodium falciparum, were selected for the interaction study with human serum albumin (HSA). The insight into the interaction of the two chemically synthesized, most potent antimalarial tetraoxane analogues (TO1 and TO2) and HSA has been scrutinized using distinct spectroscopic techniques such as. UV–visible absorption, fluorescence, time-resolved fluorescence, and circular dichroism (CD). Fluorescence quenching experiments divulged the static mode of quenching and binding constants obtained (∼104) indicated the moderate affinity of the analogues to HSA. CD confirmed the conformational changes in the serum albumin upon interaction with these analogues. Molecular docking validated the empirical results as these two analogues bind through hydrophobic interactions and hydrogen bonding with HSA. Present work first defined the binding mechanism of dispiro-tetraoxanes with HSA and thus provides a fresh insight into the drug transportation and metabolism. The present study could direct toward designing more potent tetraoxane analogues for their use in the biomedical field.

Guidelines of the Association of Anesthesiologists-Intensivists, the Interregional Non-Governmental Organization Alliance of Clinical Chemotherapists and Microbiologists, the Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy (IACMAC), and NGO Russian Sepsis Forum Diagnostics and antimicrobial therapy of the infections caused by multiresistant microorganisms

Introduction.Strains of microorganisms resistant to antimicrobial agents are commonly found in medical units throughout most regions of the world, including Russia. This leads to lower antimicrobial therapy efficacy when treating nosocomial infections. In this regard, the timely implementation of adequate antibiotic therapy is of great importance.The objective of the guidelines:To provide summarized information on contemporary approaches to microbiological diagnostics and the assessment of results, as well as the principles of rational use of antimicrobial and antifungal agents, including treatment of infections caused by multiple drug-resistant strains of microorganisms.Subjects and methods.These guidelines are based on published data obtained in the course of randomized trials, as well as information presented in the provisions of international guidelines supported by high-level evidence. The guidelines were prepared by a working group of Russian experts with extensive experience in research and practical work in this area. On October 11, 2019, the final version of the guidelines was reviewed and approved at a joint meeting of the working group and representatives of the public organizations which initiated the development of these guidelines (Association of Anesthesiologists-Intensivists, the Interregional Non-Governmental Organization Alliance of Clinical Chemotherapists and Microbiologists, the Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy (IACMAC), NGO Russian Sepsis Forum).Conclusion.The guidelines reflect an interdisciplinary consensus of approaches to the diagnostics and antibiotic therapy of infections caused by multiresistant microorganisms. The provisions set forth should be used to decide on the strategy of empirical and etiotropic therapy of the most severe infections.

Targeting Plasmodium with constrained peptides and peptidomimetics.

Malaria remains a worldwide health concern with an estimated quarter of a billion people infected and nearly half a million deaths annually. Malaria is caused by a parasite infection from Plasmodium strains which are transmitted from mosquitoes into the human host. Although several small molecule inhibitors have been found to target the early stages of transmission and prevent parasite proliferation, multiple drug resistant parasite strains have emerged and drug resistance remains a major hurdle. As an alternative to small molecule inhibition, several peptide-based therapeutics have been explored for their potential as antimalarial compounds. Chemically constrained peptides or peptidomimetics were developed to target large binding interfaces of parasite-based proteins that have historically been difficult to selectively inhibit using small molecules. Here, we review ongoing research aimed at developing constrained peptides targeting protein-protein interactions pertinent to malaria pathogenesis. These targets include Falcipain-2, the J domain of CDPK1, myosin A tail domain interacting protein, the PKA signaling pathway, and an unclear signaling pathway involving angiotensin-derived peptides. Diverse synthetic methods were also used for each target. Merging parasite biology with synthetic strategies may provide new opportunities to develop alternative methods for uncovering novel antimalarials and may offer an alternate source for targeting drug-resistant parasite strains.

Disseminated Multidrug-Resistant Tuberculosis in a Young Patient: A Rare Case Report

Drug resistance is a persistent threat to tuberculosis (TB) control program worldwide. Patients infected with multiple drug-resistant strains are less likely to become cured. Management of resistant cases is complex and presents therapeutic limitations. Patients with multidrug-resistant strains are more prone to treatment failure and progress to more chronic forms of the disease and death. According to the Global Tuberculosis Report 2018, about 3.5% of newly diagnosed patients had multidrug-resistant tuberculosis (MDR-TB) and 18% of previously treated TB cases were estimated to have MDR-TB. This case presented a rare occurrence of disseminated MDR-TB in a diabetic patient. A case of a 14-year-old female, who was an old-treated case of abdominal TB, presented with 5 months of history of fever, breathlessness, and pain in the abdomen with diabetes mellitus, in whom disseminated MDR-TB was documented with fine-needle aspiration cytology of abdominal lymph nodes and bronchoalveolar lavage fluid that showed drug-resistant TB. So this case emphasizes the importance of screening all extrapulmonary TB patients for drug resistance especially if the patient also has associated comorbid conditions.

The Microbiota in Hematologic Malignancies.

There are approximately 1.2 million new hematologic malignancy cases resulting in ~ 690,000 deaths each year worldwide, and hematologic malignancies remain the most commonly occurring cancer in children. Even though advances in anticancer treatment regimens in recent decades have considerably improved survival rates, their cytotoxic effects and the resulting long-term complications pose a significant burden on the patients and the health care system. Therefore, non-toxic treatment modalities are needed to decrease side effects. The human body is the host to approximately 40 trillion microbes, known as the human microbiota. The large majority of the microbiota is located in the gastrointestinal tract, and is primarily composed of bacteria. The microbiota plays several important physiological roles, ranging from digestive functions to immunological and neural development. Investigating the microbiota in patients with hematologic malignancies has several important implications. The microbiota affects hematopoiesis, and influences the efficacies of chemotherapy and antimicrobial treatments. Determination of the microbiota composition and diversity could be an important part of risk stratification in the future, and may also take part to personalize antimicrobial treatments. Modulation of the microbiota via probiotics or fecal transplant can potentially be involved in reducing side effects of chemotherapy, and eliminating multiple drug resistant strains in patients with hematologic malignancies.

Multiple Drug Resistant Urinary Tract Infection in Kidney Transplant Recipients: A Retrospective Cohort Study.

Urinary tract infection (UTI) is the most common infectious disease in post-kidney transplantation patients. The objective of the study was to investigate the prevalence, impact and risk factors of multiple drug resistant (MDR) UTI in kidney transplant recipients. This retrospective cohort study recruited 72 kidney transplant recipients between March 2017 and February 2018. Urine cultures performed during the 1st year of posttransplantation with reference to clinical data were evaluated. Predesigned questionnaire was used to collect data regarding demographic, transplant related, and microbiological information. Multivariate analysis was performed to ascertain risk factors of MDR UTI. Out of 72 patients, 28 (38.9%) had culture guided clinical UTI. Overall, 59 UTI episodes were noted throughout the duration of this study. Eschericia coli were found to be the most frequent uropathogen of UTI among kidney transplant recipients (n = 32, 54.2%). MDR bacteria were responsible for 27.1% (n = 16) of the post-transplantation UTI episodes among patients, with E. coli (n = 9, 56.3%) being the predominant bacterial pathogen. Most of the MDR strains of E. coli (n = 7, 77.8%) were extended spectrum beta-lactamase positive. Female gender (P <0.001), prolonged Foley's catheterization (P = 0.002), coexisting diabetes mellitus (DM) (P <0.001) and induction of anti-thymocyte globulin (ATG) therapy (P <0.001) were independently associated with high risk of MDR UTI. The allograft rejection was found to be significantly higher in patients of posttransplantation UTI with MDR uropathogen (P = 0.009). In conclusion, E. coli were the most prominent uropathogen of UTI with and without MDR pathogen in the present study. Female gender, prolonged Foley's catheterization, coexisting DM, and induction of ATG therapy were the risk factors independently associated with MDR UTI in kidney transplant recipients. MDR organisms were significantly associated with allograft rejection.

Antibiotic Resistance-as a Threat to the Future and its Role in Dentistry

The prescription of antibiotics is reaching its peak day by day in all specialities. This is causing antibiotic resistance in many bacteria along with evolution of newer multiple drug resistant strains of bacteria. If this situation continues then we would tend to ‘lose battle against the bugs’. Dentistry is a speciality commonly prescribing antibiotics all over the world. Lack of proper knowledge and lethargic attitude of many dentists contribute largely to the increasing antibiotic resistance among patients.

Combinatorial Drug Therapy for Controlling Pseudomonas aeruginosa and Its Association With Chronic Condition of Diabetic Foot Ulcer

Diabetic foot ulcer (DFU) is a major complication of diabetes mellitus, major observations of DFU cases have reported on amputation of foot region, and microbial bioburden during DFU is a major cause that affects healing of the wound regions. Pathogenic microbes are routinely isolated from these wound regions, especially Staphylococcus, Pseudomonas, Klebsiella, and Escherichia coli have been reported, whereas higher prevalence of Pseudomonas species during chronic condition in the deeper part of the wound, when left untreated, leads to gangrene. Multiple drug-resistant Pseudomonas strains are a new threat because of their biofilm-forming ability, making it more potent and incurable. Acyl homoserine lactones (AHL) are a group of signaling molecules that can regulate biofilm growth, and Las and Rhl operon generally work in tandem to initiate biofilm formation by Pseudomonas species. These signaling molecules also initiate virulence factors that correlates upregulation of inflammatory responses, and AHL can be a therapeutic target in order to prevent the efficacy of multiple drug-resistant strains that form biofilm and also can be an alternative solution against control of multiple drug-resistant strains.

Development of Protein- and Peptide-Based HIV Entry Inhibitors Targeting gp120 or gp41.

Application of highly active antiretroviral drugs (ARDs) effectively reduces morbidity and mortality in HIV-infected individuals. However, the emergence of multiple drug-resistant strains has led to the increased failure of ARDs, thus calling for the development of anti-HIV drugs with targets or mechanisms of action different from those of the current ARDs. The first peptide-based HIV entry inhibitor, enfuvirtide, was approved by the U.S. FDA in 2003 for treatment of HIV/AIDS patients who have failed to respond to the current ARDs, which has stimulated the development of several series of protein- and peptide-based HIV entry inhibitors in preclinical and clinical studies. In this review, we highlighted the properties and mechanisms of action for those promising protein- and peptide-based HIV entry inhibitors targeting the HIV-1 gp120 or gp41 and discussed their advantages and disadvantages, compared with the current ARDs.

Novel bio compactable silver nanowires and nanocubes: An effective treatment against carbapenem and vancomycin resistant strains isolated from cancer patients

Blood stream infections in the cancer patients are a critical problem which leads to considerable rate of mortality and morbidity. In view of this herein, we account the response of Poly Vinyl Pyrrolidone (PVP) coated silver nanowires (Ag-NWs) and silver nano cubes (Ag-NCs) towards carbapenem (Escherichia coli) and vancomycin (Staphylococcus aureus) resistant strains as well as to human epithelial cells. The prepared PVP capped silver nanomaterials were in the range of 80 nm (Ag-NC) and 25 nm (Ag-NW) as observed from Transmission Electron Microscopy (TEM). Though the selected strains were resistant to carbapenem and vancomycin, PVP capped Ag-NWs and Ag-NCs could inhibit the growth of these strains. These nanomaterials could break the cell wall and damage the genetic material of these strains as observed by death rate assay and alkaline comet assay. Furthermore, we have shown that toxicity of Ag-NWs and Ag-NCs precisely follows the dose retort pattern. Even though the resistant strains were susceptible to a concentration of 10 µg ml−1 of silver nanomaterials the epithelial cells were not affected by the same concentration. It is also confirmed with live dead staining assay and observed that metabolic activities of epithelial cells were not affected by a concentration of 10 µg ml−1. Overall, this work suggests that these nanomaterials can be utilized to treat the multiple drug resistant strains from cancer patients.

The YIN and YANG of lipoproteins in developing and preventing infectious arthritis by Staphylococcus aureus.

Rapid bone destruction often leads to permanent joint dysfunction in patients with septic arthritis, which is mainly caused by Staphylococcus aureus (S. aureus). Staphylococcal cell wall components are known to induce joint inflammation and bone destruction. Here, we show that a single intra-articular injection of S. aureus lipoproteins (Lpps) into mouse knee joints induced chronic destructive macroscopic arthritis through TLR2. Arthritis was characterized by rapid infiltration of neutrophils and monocytes. The arthritogenic effect was mediated mainly by macrophages/monocytes and partially via TNF-α but not by neutrophils. Surprisingly, a S. aureus mutant lacking Lpp diacylglyceryl transferase (lgt) caused more severe joint inflammation, which coincided with higher bacterial loads of the lgt mutant in local joints than those of its parental strain. Coinjection of pathogenic S. aureus LS-1 with staphylococcal Lpps into mouse knee joints caused improved bacterial elimination and diminished bone erosion. The protective effect of the Lpps was mediated by their lipid moiety and was fully dependent on TLR2 and neutrophils. The blocking of CXCR2 on neutrophils resulted in total abrogation of the protective effect of the Lpps. Our data demonstrate that S. aureus Lpps elicit innate immune responses, resulting in a double-edged effect. On the one hand, staphylococcal Lpps boost septic arthritis. On the other hand, Lpps act as adjuvants and activate innate immunity, which could be useful for combating infections with multiple drug-resistant strains.

Severe Clinical Outcomes of Tuberculosis in Kharkiv Region, Ukraine, Are Associated with Beijing Strains of Mycobacterium tuberculosis.

Genotypic variation in Beijing lineages of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB), has been associated with hyper virulence and the spread of extensively and multiple drug (X/MDR) resistant MTB strains in Eastern Europe, Central Asia, and East Asia. The clinical outcomes of 215 new cases of TB among the population of the Kharkiv region of Eastern Ukraine were analyzed to uncover factors associated with severe infection. Infecting MTB strains were profiled by 5 locus exact tandem repeats (ETRs) and 15 locus mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) genotyping. Among diverse MTB genotypes discovered in Ukraine, the Beijing genotype (MIRU-VNTR 42425) was significantly associated with risk factors for severe outcomes of disease in the study population, including TB/HIV co-infection and treatment failure. Strain replacement (superinfection) was observed in 10 patients, suggesting repeated exposure to novel MTB strains in hospital or community settings. Inclusion of MTB genotyping data may identify at-risk patients and improve treatment adherence to prevent X/MDR development for effective public health response against tuberculosis in Ukraine.

Development of a technological platfom for creating innovative anti-tb drugs effective against multi-drug-resistant strains

This article tackles the issue of the growing morbidity and mortality caused by multi-drug-resistant (extreme drug-resistant) tuberculosis (TB). This issue is aggravated by the alarming rise of immunocompromized patients and immigration worldwide. In order to solve this problem, an interdisciplinary approach is needed. Here we offer to: (1) develop innovative diagnostic techniques for identifying dangerous lineages of TB with mutations and drug resistance genes; (2) develop antibiotics with new modes of action effective against multiple drug resistance and extreme drug-resistant strains of TB and HIV; (3) develop new genetically engineered vaccines; and, (4) develop new vaccine adjuvants based on probiotic Lactobacillus and Bifidobacterium stains, with selective immunomodulatory activity.

Identification and characterization of lung commensal bacteria that modulate immune response in Tuberculosis

Abstract Tuberculosis (TB) is still one of the deadliest infectious diseases in humans. As TB disease is driven by exacerbation of the immune response, promising approaches include host-targeting therapies aiming at controlling the balance between pathogen eradication and limitation of the inflammation in order to prevent immunopathology. Such immune modulation has been observed through modification of the gut-microbiota compartment with oral administration of specific bacterial strains (i.e. probiotics) in other respiratory diseases. In TB, a dysbiosis of the microbiota is observed in patients, and microbiota perturbation in mice increases susceptibility to Mycobacterium tuberculosis (Mtb). Here, we assessed whether bacterial strains isolated from the recently described lung microbiota could have a local impact on Mtb infection by protecting against immune dysfunction for the host benefit. Through intranasal administration in mice, we identified different microbiota strains isolated from mouse lungs with a strong ability to modulate the lung T cell compartment. The same in vivo approach in Mtb-infected mice revealed one strain with a remarkable capacity to diminish Mtb infection-associated lung immunopathology, accompanied by a specific immune signature characterized by an increase level of regulatory T cells sharing surprisingly T-helper 17 cell markers. Collectively, this work may contribute to the design of host-directed therapies to reduce the destructive inflammatory response in TB, without further fomenting the occurrence of multiple-drug resistant Mtb strains. It will also shed light on poorly described populations in the lungs such as the RORgt+ Foxp3+ biTregs and their interactions with the microbiota.

Synthesis and evaluation of new quinazolin-4(3H)-one derivatives as potent antibacterial agents against multidrug resistant Staphylococcus aureus and Mycobacterium tuberculosis

Staphylococcus aureus and Mycobacterium tuberculosis are major causative agents responsible for serious nosocomial and community-acquired infections impacting healthcare systems globally. Over several decades, these pathogens have developed resistance to multiple antibiotics significantly affecting morbidity and mortality. Thus, these recalcitrant pathogens are amongst the most formidable microbial pathogens for which international healthcare agencies have mandated active identification and development of new antibacterial agents for chemotherapeutic intervention. In our present work, a series of new quinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP pathogens and pathogenic mycobacteria. The experiments revealed that 4'c, 4'e, 4'f and 4'h displayed selective and potent inhibitory activity against Staphylococcus aureus with MIC values ranging from 0.03-0.25 μg/mL. Furthermore, compounds 4'c and 4'e were found to be benign to Vero cells (CC50 = >5 μg/mL) and displayed promising selectivity index (SI) > 167 and > 83.4 respectively. Additionally, 4'c and 4'e demonstrated equipotent MIC against multiple drug-resistant strains of S. aureus including VRSA, concentration dependent bactericidal activity against S. aureus and synergized with FDA approved drugs. Moreover, compound 4′c exhibited more potent activity in reducing the biofilm and exhibited a PAE of ∼2 h at 10X MIC which is comparable to levofloxacin and vancomycin. In vivo efficacy of 4'c in murine neutropenic thigh infection model revealed that 4'c caused a similar reduction in cfu as vancomycin. Gratifyingly, compounds 4d, 4e, 9a, 9b, 14a, 4'e and 4'f also exhibited anti-mycobacterial activity with MIC values in the range of 2-16 μg/mL. In addition, the compounds were found to be less toxic to Vero cells (CC50 = 12.5->100 μg/mL), thus displaying a favourable selectivity index. The interesting results obtained here suggest the potential utilization of these new quinazolin-4(3H)-one derivatives as promising antibacterial agents for treating MDR-Staphylococcal and mycobacterial infections.

NATURAL ANTIMICROBIALS IN THE PIPELINE AND POSSIBLE SYNERGISM WITH ANTIBIOTICS TO OVERCOME MICROBIAL RESISTANCE

The unresponsive use of antibiotics led to the appearance of multiple drug-resistant bacteria strains. Studying the mechanism by which bacteria can resist antibiotics, the so called quorum sensing and biofilm formation, enabled the researchers to find bioactive compounds, derived from eukaryotes and prokaryotes. The disrupt of this mechanism is called quorum sensing inhibitors or quorum quenchers. This article provides an overview on the current research done on such bioactive compounds, the possible use of them as antibiotic alternatives, what are the advantage and disadvantages, the source from which it has been extracted, and how it may succeed to overcome bacterial resistance. The recommendation of researchers is to use some of these natural antimicrobial compounds combined to lower doses of antibiotics for treatment, the fastest way to limit the adverse effects of the exploitation of antibiotics and to avoid bacterial resistance.

A Small RNA Transforms the Multidrug Resistance of Pseudomonas aeruginosa to Drug Susceptibility

Bacteria with multiple drug resistance (MDR) have become a global issue worldwide, and hundreds of thousands of people’s lives are threatened every year. The emergence of novel MDR strains and insufficient development of new antimicrobial agents are the major reasons that limit the choice of antibiotics for the treatment of bacterial infection. Thus, preserving the clinical value of current antibiotics could be one of the effective approaches to resolve this problem. Here we identified numerous novel small RNAs that were downregulated in the MDR clinical isolates of Pseudomonas aeruginosa (P. aeru), and we demonstrated that overexpression of one of these small RNAs (sRNAs), AS1974, was able to transform the MDR clinical strain to drug hypersusceptibility. AS1974 is the master regulator to moderate the expression of several drug resistance pathways, including membrane transporters and biofilm-associated antibiotic-resistant genes, and its expression is regulated by the methylation sites located at the 5′ UTR of the gene. Our findings unravel the sRNA that regulates the MDR pathways in clinical isolates of P. aeru. Moreover, transforming bacterial drug resistance to hypersusceptibility using sRNA could be the potential approach for tackling MDR bacteria in the future.